Method and mixture to form functionalized cyclic compounds

ABSTRACT

A method for producing a homocyclic or heterocyclic compound includes reacting a compound of formula (I) with a compound of formula (II) in presence of a base:In formula (I), B is an unsaturated moiety selected from substituted or unsubstituted vinylene, ethynylene, aryleneethynylene, substituted or unsubstituted arylenevinylene, and a combination thereof, the vinylene or arylenevinylene has n (=0, 1 or 2) substituent(s) R2, G is an electron-withdrawing group, R1 is hydrogen or a substituent, and two of R1, R2 and G may joint together to form a ring. In formula (II), R3 and R4 are independently hydrogen or a substituent, R5 is an electron-withdrawing group, and two of R3, R4 and R5 may joint together to form a ring. The conjugate acid of the base has a pKa in the range of 1 to 15.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a divisional application of and claims the prioritybenefit of U.S. application Ser. No. 16/362,709, filed on Mar. 25, 2019,now allowed. The entirety of the above-mentioned patent application ishereby incorporated by reference herein and made a part of thisspecification.

BACKGROUND OF THE INVENTION Field of Invention

This invention relates to functionalized organic compounds and theirpreparation, and more particularly relates to a method for forminghighly functionalized cyclic compounds (e.g., cyclopentenes, andcyclopentadiene oximes).

Description of Related Art

A great variety of medicinal or bioactive compounds present afunctionalized cyclopentene moiety within their structure. For example,a functionalized cyclopentene core having a quaternary allylic carbonbearing a carboxamide group and an electron-withdrawing group is astructural motif of tetrahydropyranal cyclopentyl benzylamide (TCB)compounds. TCB have been shown to regulate the activity of chemokinereceptors, and their use has been suggested in the treatment of diseasesor conditions associated with inflammations or infections (cf. Butora etal., WO 2004/041161 A2). Similarly, compounds presenting afunctionalized cyclopentadienone-oximes moiety have shown modulatoractivity for peroxisome proliferated activated receptors (PPAR, cf.Cheon et al., WO 2005/100303 A1).

Currently available synthetic routes towards functionalized cyclopenteneor cyclopentadienone-oxime derivatives tend to be unsatisfactory asinvolving numerous reaction steps, using expensive catalysts orreagents, and being applicable for only limited substrate scope. Forexample, Vink et al. (Biotechnol. J., 2006, 7, 569) obtainedfunctionalized cyclopentene derivatives including a quaternary carboncenter bearing a carboxamide group and another electron withdrawinggroup from malononitrile via double α-allylation, ring-closuremetathesis and enzyme-differentiated hydrolysis. Products including asimilar core were obtained starting from a cyanoesteramide by Gao et al.(Chem Cat Chem, 2016, 8, 3466), via double α-allylation and ring-closuremetathesis, or by Ziegler et al. (Angew. Chem. Int. Ed., 2014, 53,13183) via a phosphine-catalyzed [4+1] annulation with an asymmetricallenoate. In all the aforementioned cases, the stereogenic quaternarycarbon is in the β-position to the vinyl group, rather than in thedesirable allylic position. Concerning the cyclopentadienone oximemoieties, these have been chiefly prepared by reaction of hydroxylaminewith cyclopentadienones, which might require several steps to beprepared (cf., in the case of indenones, Cheon et al., U.S. Pat. No.7,745,439 B2).

In light of the interesting biological activity displayed, there is agreat need of more straightforward routes towards functionalizedcyclopentenes and cyclopentadienone oxime derivatives. As at least inthe case of cyclopentenes derivatives where the formation of newstereogenic centres is involved, reaction routes that producespredominantly a specific pair of diastereoisomer would be, in general,preferred.

SUMMARY OF THE INVENTION

Accordingly, this invention provides an effective, low-cost,environmentally friendly method for forming functionalized unsaturatedhomocyclic or heterocyclic compounds, such as cyclohexenes,cyclopentenes or cyclopentadienone oximes derivatives.

This invention also provides an effective, low-cost, environmentallyfriendly method for forming functionalized cyclopentadienone oximesderivatives starting from functionalized cyclopentenes.

This invention further provides a reaction mixture to formfunctionalized cyclopentenes or cyclopentadienone oximes.

This reaction is based on the effectiveness of mild bases to act as dualfunctional organocatalysts to promote a cascade Michael reaction betweena Michael acceptor and a dual functional compound that contains both aMichael donor moiety and a less reactive Michael acceptor moiety to forma cyclic compound.

In a method to produce a homocyclic or heterocyclic compound, a compoundof formula (I) is reacted with a compound of formula (II) in presence ofa base.

In formula (I), B is an unsaturated moiety, selected from the groupconsisting of substituted or unsubstituted vinylene, ethynylene,aryleneethynylene, substituted or unsubstituted arylenevinylene, and acombination thereof, such as vinylene-ethynylene (e.g., an enynemoiety), diene, triene, tetraene, polyene, diacetylene, triacetylene,arylene-vinylene, vinylene-arylene-vinylene, arylene-ethynylene,ethynylene-arylene-ethynylene, and ethylene-arylene-ethynylene. Thevinylene or arylenevinylene has n substituent(s) R², wherein n is 0, 1or 2, and when n is 2, the two R² may be the same or different, and mayjoint together to form a ring. G is an electron-withdrawing groupselected from the group consisting of oxygen-containingelectron-withdrawing groups, nitrogen-containing electron-withdrawinggroups, sulfur-containing electron-withdrawing groups,phosphorous-containing electron-withdrawing groups, electron-withdrawingaromatic groups, electron-withdrawing heteroaromatic groups,halogen-substituted alkyl groups, and halogen atoms.

R¹ is hydrogen or a substituent, and may joint together with R² to forma ring. Likewise, either R¹ or R² may joint together with G to form aring. In formula (II), each of R³ and R⁴ is independently hydrogen or asubstituent, and R³ and R⁴ are the same or different. R⁵ is anelectron-withdrawing group comprising the permissible group of G. Two ofR³, R⁴ and R⁵ may joint together to form a ring. In some embodiments,the conjugate acid of the base has a pK_(a) in the range from 1 to 15.

The inventor has found out that the reaction might proceed with higherdiastereoselectivity when the base is a mild base that can promotecoordination between the proton on the activated methylene of thecompound of formula (II) and the carbonyl group of the same compound. Insome derivative methods of this invention, the base comprises afluoride-containing ion. In some other derivative method, the base is anorganic fluoride salt such as a tetraalkylammonium fluoride compound.

Without being bound to or limited by any chemical theory, it is possiblethat the base promotes the reaction by hydrogen-bonding to the mostacidic and positively charged hydrogen of the compound of formula (II),namely the hydrogen bonded to the activated methylene being attached tothe cyano and R⁵ groups. It might be envisioned that the H-bondinginteraction between the base and the activated methylenic protonpolarizes the C—H bond, thus increasing the ionization degree and theacidity of the proton. The proton might then be able to coordinate theoxygen of the carbonyl group moiety, forming a transient five-memberedring adduct (VII).

In formula (VII), A represents the base or a constituent thereof usedwithin the reaction, for example a fluoride anion.

In some methods according to this invention, the reaction is carried outin a solvent. In some embodiments of this invention, the solvent is anaprotic solvent that is lacking of N—H or O—H protons, so that solvationinteraction between the base and the solvent can be avoided. In somealternative embodiments of this invention, the solvent has a dielectricconstant of at least 6, to better polarize the C—H bond of the activatedmethylene carbon in the compound of formula (II). In some alternativeembodiments, an anhydrous solvent is used, to prevent solvationinteraction of water impurities with the base.

In some embodiments, the reaction is stirred at a temperature in a rangefrom 0° C. to 45° C.

In some embodiments, a product of the reaction of the compound offormula (I) with the compound of formula (II) is a cyclopentene compoundof formula (III).

In formula (III), G, n, R¹, R², R³, R⁴, and R⁵ are the same as informulae (I) and (II).

In some embodiments, the cyclopentadiene compound of formula (III) isobtained as a racemic mixture.

Without being bound to or limited by any chemical theory or mechanisticproposal, it is possible that the activated methylene carbon in theadduct (VII) can act as a nucleophilic center, whilst the carbonyl groupis an activated electrophilic center. Adduct (VII) might rapidly undergoa sequence of two Michael reactions with a compound of formula (I) toform a cyclic compound of formula (VIII).

In formula (VIII), G, R¹, R², R³, R⁴, R⁵ and n can be the samesubstituents or assume the same values as in compounds of formulae (I)and (II). The dashed line indicates that the corresponding bond can be asingle or a double bond.

Upon formation of the cyclic compound (VIII) the relativestereochemistry of the substituents R¹ and G is fixed. When B in formula(I) is a trans double bond, the cyclic compound (VIII) is acyclopentanol, and R¹ and G maintain their trans relationship within thecycle. It is possible that in the conditions disclosed by the presentinvention the two-steps reaction between the compound of formula (I) andthe compound of formula (II) is fast enough or even concerted, leadingto a retention of the stereochemistry of the compound of formula (I) inthe compounds of formulae (VIII) and (III).

When the bond corresponding to the dashed bond in formula (VIII)indicates a single bond, the cyclic compound (VIII) might evolve byhydrolysis of the cyano group and elimination of the hydroxylsubstituent to form a cyclopentene derivative of formula (III). It ispossible that the hydroxylic group formed from the carbonyl group ofcompound (II) interacts with the cyano group in cis to the same hydroxylgroup, for example through protonation or hydrogen bonding interaction,thereby activating the cyano group towards a nucleophilic attack of thehydroxyl oxygen to form a bicyclic compound (IX). It can be envisionedthat the base might promote the proton transfer or the hydrogen bondinginteraction by acting as an intermediary.

In formula (IX), G, R¹, R², R³, R⁴, R⁵ and n can be the samesubstituents or assume the same values as in compounds of formulae (I)and (II).

The imino nitrogen of the compound of formula (IX) might be activatedthrough protonation yielding the corresponding cation, which mightevolve through base-assisted elimination (E2) or unimolecularelimination (E1) to form a cyclopentene compound of formula (III).Without being limited to or bound by any chemical theory or mechanistichypothesis, a transfer of the hydroxyl group to the cyano group in cisconfiguration in the cyclic compound (VIII) might explain the observeddiastereoselectivity in the compound of formula (III).

In some embodiments, a diastereoisomer of formula (III-B) is also formedduring the reaction.

The compound of formula (III-B) is an epimer of the compound of formula(III) at the allylic quaternary carbon. In some embodiments of thepresent invention, the reaction produces larger amounts of the compoundof formula (III) than its epimer (III-B). The compound (III) and theepimer (III-B) are formed as a racemic mixture in absence of chiralinduction.

In some embodiments, a cyclopentadiene compound of formula (III), inwhich G is NO₂, R⁴ is H, and n is 0 or 1, may be further reacted toobtain a compound of formula (IV).

In formula (IV), each of R¹, R², R³, R⁵, and n are the same as in thecorresponding compound of formula (III). In some embodiments, thecompound of formula (III) is isolated from the reaction mixture beforebeing reacted to form the compound of formula (IV). In some alternativeembodiments, the reaction may be carried to directly obtain the compoundof formula (IV) skipping the purification step of the compound offormula (III). As a non-limiting example, once it is decided thatformation of the compound of formula (III) is completed or that thereaction has progressed enough, the reaction mixture might be subjectedto the condition of formation of the compound of formula (IV) withoutany intermediate purification step. In some embodiments, compound (IV)may be obtained directly from the reaction mixture of compounds (I) and(II) by performing the reaction directly at effective elevatedtemperatures.

In some alternative method of this invention, a compound of formula (V)is obtained by reacting a compound of formula (VI).

In formula (V) and in formula (VI), each of R⁶, R⁷ and R⁸ isindependently a hydrogen or a substituent, R⁶, R⁷, and R⁸ are the sameor different. R⁹ is hydrogen, a substituent selected from thepermissible groups of R⁶, R⁷ and R⁸, or an electron withdrawing groupselected from the aforementioned permissible groups of G. Either R⁹ andR⁶, or R⁹ and R⁷, or R⁹ and R⁸ may joint together to form a ring.

In some embodiments of the present disclosure, the compound of formula(VI) is reacted at a temperature in a range between 50° C. and 140° C.

In some alternative embodiments, the compound of formula (VI) is reactedin presence of a base, and a conjugated acid of the base has a pK_(a) inthe range of 1 to 15, more preferably in the range of 1 to 13.5. In someembodiments, the base comprises a fluoride-containing ion. In someembodiments, the molar ratio of the base to the compound of formula (VI)is in the range of 0.001 to 10, more preferably in the range of 0.001 to0.5.

According to some embodiments of the present invention, a reactionmixture is provided comprising a compound of formula (I), a compound offormula (II), and a base.

Formula (I) and (II) are as defined above. The conjugate acid of thebase has a pK_(a) in the range of 1 to 15, more preferably in the rangeof 1 to 13.5.

In some embodiments, the reaction might proceed with higherdiastereoselectivity when the base is a mild base that can promotecoordination between the proton on the activated methylene of thecompound of formula (II) and the carbonyl group of the same compound offormula (II). In some reaction mixtures according to the presentinvention, the base comprises a fluoride-containing ion. In somereaction mixtures, the base is an organic fluoride salt, such as atetraalkylammonium fluoride compound.

A reaction mixture according to some embodiments of the presentinvention may include an aprotic solvent. In some alternativeembodiments, the solvent may have a dielectric constant of at least 6.In some alternative embodiments, the solvent may be anhydrous.

A reaction mixture according to some embodiments of the presentdisclosure may include a compound of formula (VI) and a base.

Formula (VI) is as defined above. The conjugated acid of the base has apK_(a) in the range from 1 to 15, more preferably in a range of 1 to13.5.

In some embodiments, the base in the reaction mixture comprises afluoride-containing ion.

In some embodiments, the molar ratio of the base to the compound offormula (VI) is in the range of 0.001 to 10, more preferably in a rangeof 0.001 to 0.5.

Because the disclosed method does not use air- and moisture-sensitivereagents, the required chemical handling is relatively easy. Moreover,since the method needs a simple production facility and themanufacturing process is simple and safe, the manufacturing cost is low.In addition, since at least part of the reaction can be effectivelyconducted at ambient temperature, the method is also energy-saving.Also, the manufacturing process of the method of this invention isheavy-metal free, so that the method is environmentally friendly.

In order to make the aforementioned and other objects, features andadvantages of this invention comprehensible, a preferred embodimentaccompanied with figures is described in detail below.

It should be noted that although mechanistic hypotheses concerning thepath followed by the reaction are presented, such discussions areprovided in the attempt to rationalize the role of the individualcomponents included in the method and the effects observed on thereaction outcome. Under no circumstance should these discussions beconstrued as limitations of the present disclosure. In other words, thedisclosure is not intended to be bound to or limited by any chemicaltheory, nor by any reaction mechanism suggested or discussed herein.

For the purpose of the present disclosure, reactions run at ambienttemperatures are run without exercising an active control of thetemperature (for example via thermostats, heating, or cooling baths).

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the crystal structure of compound (III-1).

FIG. 2 shows the crystal structure of compound (III-16).

FIG. 3 shows the crystal structure of compound (III-B-16).

FIG. 4 shows the crystal structure of compound (X-1).

FIG. 5 shows the crystal structure of compound (X-2).

FIG. 6 shows the crystal structure of compound (X-3).

FIG. 7 shows the crystal structure of compound. (IV-1)

FIG. 8 shows the crystal structure of compound (IV-3)

DESCRIPTION OF EMBODIMENTS

It is first noted that the term “a compound of formula (I)” is sometimescalled “a compound (I)” hereafter for simplicity. The same rule appliesto formulae (II) to (X) and specific examples thereof. For the sake ofsimplicity, unless otherwise indicated compounds of formula (III)indicates compounds having the same configuration as shown in formula(III) at the three stereogenic centers and their enantiomers. Similarly,unless otherwise indicated, compounds of formula (III-B) indicatescompounds having the same configuration as shown in formula (III-B) atthe three stereogenic centers and their enantiomers.

The group B in the compound of formula (I) is an unsaturated moiety,selected from substituted or unsubstituted vinylene, ethynylene,aryleneethynylene, substituted or unsubstituted arylenevinylene, and thecombination thereof, such as vinylene-ethynylene (e.g. an enyne moiety),diene, triene, tetraene, polyene, diacetylene, triacetylene,arylene-vinylene, vinylene-arylene-vinylene, arylene-ethynylene,ethynylene-arylene-ethynylene, and ethylene-arylene-ethynylene. Thevinylene or arylenevinylene has n substituent(s) R², wherein n is 0, 1or 2, and when n is 2, the two R² may be the same or different, and mayjoint together to form a ring.

The group G in the above formulae (I)-(III) is an electron withdrawinggroup selected from the group consisting of oxygen-containingelectron-withdrawing groups, nitrogen-containing electron-withdrawinggroups, sulfur-containing electron-withdrawing groups,phosphorous-containing electron-withdrawing groups, electron-withdrawingaromatic and heteroaromatic groups, halogen-substituted alkyl groups,and halogen atoms.

Examples of the oxygen-containing electron-withdrawing groups include[—C(═O)R¹⁰], wherein R¹⁰ is selected from hydrogen, alkyl, aryl,heteroaryl, alkoxy, aryloxy, heteroaryl oxy, alkylthio, arylthio,heteroarylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino,alkylarylamino, and hydroxyl groups.

Examples of the nitrogen-containing electron-withdrawing groups includecyano, nitro, and —C(═N—R¹¹)R¹², wherein R¹¹ and R¹² are the same ordifferent in each occurrence and are independently selected fromhydrogen, alkyl, aryl, and heteroaryl groups.

Examples of the sulfur-containing electron-withdrawing groups include—S(═O)R¹³ and —S(═O)₂R¹⁴. R¹³ and R¹⁴ are the same or different at eachoccurrence and are independently selected from hydrogen, alkyl, aryl,heteroaryl, alkoxy, aryloxy, heteroaryl oxy, amino, alkylamino,dialkylamino, arylamino, diarylamino, alkylarylamino, and hydroxylgroups.

Examples of the phosphorous-containing electron-withdrawing groupsinclude —P(═O)R¹⁵R¹⁶ and —P(═O)₂R¹⁷. R¹⁵, R¹⁶ and R¹⁷ are the same ordifferent and are independently selected from hydrogen, alkyl, aryl,heteroaryl, alkoxy, aryloxy, heteroaryloxy, alkylthio, arylthio,heteroarylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino,alkylarylamino, and hydroxyl groups.

Examples of the electron-withdrawing aromatic groups include aryl ringshaving one or more electron-withdrawing groups, and electron-withdrawingheteroaryl groups. Examples of the aryl rings having one or moreelectron-withdrawing groups include —CF₃-substituted aryl,NO₂-substituted aryl, carbonyl-substituted aryl, halogen-substitutedaryl, and cyano-substituted aryl. Examples of the electron-withdrawingheteroaryl groups include the substituent ring derived from pyridine,pyrimidine, imidazole, purine, adenine, guanine, cytosine, uracil,thymine, and histidine.

Examples of the halogen-substituted alkyl groups includeα-halo-substituted alkyl groups, α-dihalo-substituted alkyl groups,α-trihalomethyl groups, perhaloalkyl groups, and the like.

The preferred electron withdrawing group G is selected from the groupconsisting of NO₂CN, formyl, acyl, alkylacyl, arylacyl, alkoxycarbonyl,aryloxycarbonyl, amido, carboxy, ester, amide, alkanoate, alkanoic acid,nitrile, alkanal, alkanone, sulfinyl, sulfonyl, sulfonate,alkylphosphine oxide, arylphosphine oxide, alkylphosphinate,arylphosphinate, alkylphosphonate, or arylphosphonate.

<Substituent R¹ and R² in Formulae (I), (III), and (IV) and R³, R⁴, andR⁵ in Formulae (II), (III), and (IV)>

Each of R¹ and R² in formulae (I), (III) and (IV) is independentlyselected from the group consisting of hydrogen, deuterium, substitutedand unsubstituted alkyl, alkenyl, alkynyl, alkenynyl, aryl, alkylaryl,arylalkyl, allyl, benzyl, cycloalkyl, cycloalkenyl, cycloalkynyl,cycloalkenynyl, alkanoyl, aryloyl, alkylsilyl, arylsilyl, alkoxysilyl,aryloxysilyl, alkoxycarbonyl, aryloxycarbonyl, heterocyclic ring,heteroaromatic ring, alkylsulflnyl, arylsulflnyl, alkylsulfonyl,arylsulfonyl, derivatives of various acid functional groups includingphosphonic acid, phosphinic acid, boric acid, carboxylic acid, sulfinicacid, sulfonic acid, sulfamic acid, and amino acid, wherein the acidderivatives may include ester, amide and metal salt; aliphatic moietieshaving a repeating unit of —(OCH₂CH₂)_(q)OCH₃,—(OCH₂CH(CH₃))_(q)OCH₃—(CH₂)_(q)CF₃, —(CF₂)_(q)CF₃ or —(CH₂)_(q)CH₃,wherein q≥1; and aliphatic chains having a moiety of (OR¹⁸)_(r)OR¹⁹,wherein R¹⁸ is a divalent C₁₋₇ alkylene moiety, R¹⁹ is C₁₋₂₀ alkyl, and1≤r≤50. All the above mentioned substituent groups may be furthersubstituted with allowable functional groups, such as ester, amino acid,halo, epoxy, amino, amido, acyl, organosilyl, organotin, organogermyl,nitro, alkoxy, aryloxy, alkyl, aryl, heteroaryl, alkylthio,heteroarylthio, arylthio groups, and derivatives of various acidfunctional groups including phosphonic acid, phosphinic acid, boricacid, carboxylic acid, sulfinic acid, sulfonic acid, sulfamic acid, andamino acid, wherein the acid derivatives may include ester, amide andmetal salt.

The groups R¹ and R², or R¹ and the substituent group of G, or R² andthe substituent group of G may joint together to form a substituted orunsubstituted alkylene, alkenylene, or alkynylene chain completing aheteroalicyclic or alicyclic ring system, which may include one or moreheteroatoms and/or divalent moieties such as nitrogen, sulfur, sulfinyl,sulfonyl, phosphorus, selenium, tellurium, ester, carbonyl, and oxygen,wherein permissible substituents are the aforementioned functionalgroups.

Each R³ and R⁴ in formulae (II), (III), and (IV) is selected from thepermissible groups listed above for R¹ and R².

Each R⁵ in formulae (II), (III), and (IV) is selected from thepermissible electron-withdrawing groups listed above for G.

Two of the groups R³, R⁴, and R⁵ may joint together to form asubstituted or unsubstituted alkylene, alkenylene, or alkynylene chaincompleting a heteroalicyclic or alicyclic ring system, which may includeone or more heteroatoms and/or divalent moieties such as nitrogen,sulfur, sulfinyl, sulfonyl, phosphorus, selenium, tellurium, ester,carbonyl, and oxygen, wherein permissible substituents are theaforementioned functional groups.

<Substituents R⁶, R⁷, R⁸ and R⁹ in Formulae (V) and (VI)>

Each R⁶, R⁷, R⁸ and R⁹ in formulae (V) and (IV) is independentlyselected from the permissible groups listed above for R¹ and R².

Two of the groups R⁶, R⁷, R⁸, and R⁹ may joint together with each otherto form a substituted or unsubstituted alkylene, alkenylene, oralkynylene chain completing a heteroalicyclic or alicyclic ring system,which may include one or more heteroatoms and/or divalent moieties suchas nitrogen, sulfur, sulfinyl, sulfonyl, phosphorus, selenium,tellurium, ester, carbonyl, and oxygen, wherein permissible substituentsare the aforementioned functional groups. R⁹ is hydrogen, a substituentselected from the permissible groups listed above for R⁶, R⁷, and R⁸, oran electron withdrawing group selected from the aforementionedpermissible groups of G.

<Aromatic Groups for R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ in Formulae(I) to (VI)>

As described above, each of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, and R⁹ informulae (I) to (VI) can be a substituted or unsubstituted, mono- orpoly-nuclear, aryl or heteroaryl. The aryl and heteroaryl preferablydenote a mono-, bi- or tricyclic aromatic or heteroaromatic group withup to 25 carbon atoms that may also comprise condensed rings and isoptionally substituted. Preferred aryl groups include, withoutlimitation, benzene, biphenylene, triphenylene, naphthalene, anthracene,binaphthylene, phenanthrene, pyrene, dihydropyrene, chrysene, perylene,tetracene, pentacene, benzpyrene, fluorene, indene, indenofluorene,spirobifluorene, and the like. Preferred heteroaryl groups include,without limitation, 5-membered rings like pyrrole, pyrazole, imidazole,1,2,3-triazole, 1,2,4-triazole, tetrazole, furan, thiophene,selenophene, oxazole, isoxazole, 1,2-thiazole, 1,3-thiazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole,1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole,1,3,4-thiadiazole, 6-membered rings like pyridine, pyridazine,pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine,1,2,4,5-tetrazine, 1,2,3,4-tetrazine, 1,2,3,5-tetrazine, and fusedsystems like carbazole, indole, isoindole, indolizine, indazole,benzimidazole, benzotriazole, purine, naphthimidazole,phenanthrimidazole, pyridimidazole, pyrazinimidazole,quinoxalinimidazole, benzoxazole, naphthoxazole, anthroxazole,phenanthroxazole, isoxazole, benzothiazole, benzofuran, isobenzofuran,dibenzofuran, quinoline, isoquinoline, pteridine, benzo-5,6-quinoline,benzo-6,7-quinoline, benzo-7,8-quinoline, benzoisoquinoline, acridine,phenothiazine, phenoxazine, benzopyridazine, benzopyrimidine,quinoxaline, phenazine, naphthyridine, azacarbazole, benzocarboline,phenanthridine, phenanthroline, thieno[2,3b]thiophene,thieno[3,2b]thiophene, dithienothiophene, dithienopyridine,isobenzothiophene, dibenzothiophene, benzothiadiazothiophene, orcombinations thereof. The heteroaryl groups may be substituted withallowable functional groups, such as acid, ester, amino acid, halo,epoxy, amino, silyl, nitro, alkoxy, aryloxy, arylthio, arylthio, alkyl,fluoro, fluoroalkyl, or further aryl or heteroaryl substituents.

<Base Catalyst>

Useful bases for implementing this invention include bases that have aconjugate acid with a pK_(a) in the range from 1 to 15, more preferablyin a range of 1 to 13.5. Exemplary bases includes bases containingcarbonate and bicarbonate anions, nitrogen-containing bases such as1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo[2.2.2]octane(DABCO), amines, alkyl- or aryl-substituted amines, substituted andunsubstituted anilines and poly anilines, A-substituted poly anilines,N,N′-diphenyl-1,4-phenylenediimine (PDI), oligomeric anilines,phenyl-caped oligomeric anilines; A-containing heterocycles such assubstituted and unsubstituted pyridines, pyrimidines, imidazoles,purines, adenines, guanines, histidines, pyrrolidine, piperidine, andmorpholine; fluoride containing bases, including organic fluoride salts,such as alkylammonium fluorides, and tetraalkylammonium fluorides;inorganic fluoride salts containing cations of alkali metals, alkalineearth metals, transitional metals, or main group elements, such assodium fluoride, potassium fluoride, caesium fluoride, calcium fluoride,magnesium fluoride, copper(II) fluoride, cuprous fluoride, silverfluoride, and ammonium fluoride; acid fluoride salts that containbifluoride anion (e.g., HF₂ ⁻) or other polymeric fluoride anions(H_(x)F_(x+1) ⁻, such as H₂F₃ ⁻, H₃F₄ ⁻, H₄F₅ ⁻); and trifluoride salts(F₃ ⁻). Preferred bases are the fluoride containing bases, such asorganic fluoride salts, inorganic fluoride salts, acid fluoride salts.More preferred bases are organic fluoride salts such astetraalkylammonium fluorides.

The bases described above can be used either alone or as a mixture withone or more bases. The amount of base used to implement this inventioncan vary widely. Amounts of bases as low as 0.01 mol % (with respect tothe moles of compound of formula (II) used) are effective in promotingthe reaction. Increasing the amount of base in general leads to areduction in the reaction times, with only small effects on the yieldand diastereoselectivity of the reaction. In some embodiments, the molarratio of the base to the compound of formula (II) is in the range of0.001 to 10, more preferably in the range of 0.001 to 0.5. Use of toostrong a base might result in complex reaction mixtures and loss ofdiastereoselectivity.

<Solvents>

The reactive starting molecules used in the present disclosure can beeither in a neat liquid form, a pure solid form, or a molten form, or asa solute form dissolving or dispersing in a given solvent medium. Theresultant mixture may form a single miscible liquid phase at the firstmoment, or it can form initially a biphasic liquid/liquid orliquid/solid mixture that may then gradually turn into a monophasicmixture as the reaction proceeds with time.

Any solvent or solvent mixture can be used as the desirable solventmedium in implementing the present invention as long as it can helpdissolve or disperse, mix or contact the reactive starting molecules andthe base catalyst. Illustrative useful solvents include alcohols, linearand cyclic ethers, esters, hydrocarbons, halogen-containinghydrocarbons, substituted aromatics, ketones, amides, nitriles,carbonate esters, sulfoxides and other sulfur-containing solvents,nitroalkanes, and mixtures thereof.

Exemplary alcohols include methanol, ethanol, isopropanol, and the like.Illustrative linear and cyclic ethers include tetrahydrofuran (THF),tetrahydropyran, 2-methyltetrahydrofuran, diethyl ether, diglyme, glyme,dipropyl ether, dibutyl ether, methyl butyl ether, diphenyl ether,dioxane, diethylene glycol, ethylene glycol (EG), and the like.Illustrative aliphatic hydrocarbons include hexane, heptane, octane,nonane, decane, and the like. Exemplary halogen-containing hydrocarbons,include dichloromethane, chloroform, 1,2-dichloroethane, carbontetrachloride, dichloroethane, dichloroethene, dibromoethane,trichloroethane, tetrachloroethane, tetrachloroethene, tribromoethane,and the like. Illustrative substituted aromatics include xylene,anisole, toluene, benzene, cumene, mesitylene, phenol, cresol,nitrobenzene, dichlorobenzene, chlorobenzene, and the like. Exemplaryketones include acetone, propanone, butanone, pentanone, hexanone,heptanone, octanone, acetophenone, and the like. Exemplary estersinclude ethyl acetate, methyl acetate, methyl propanoate, methylbutanoate, methyl pentanoate, and the like. Illustrative amides includeN,N-dimethylformamide (DMF), N,N-dimethylacetamide, N-methyl acetamide,acetamide, formamide, N-methyl-2-pyrrolidinone, 2-pyrrolidinone and thelike. Exemplary nitriles include acetonitrile, propionitrile,benzonitrile, butyronitrile, and the like. Illustrative sulfoxides andother sulfur containing solvents include dimethylsulfoxide (DMSO),dimethylsulfone, and the like. Illustrative nitro substituted alkanesand aromatics include nitromethane, nitroethane, nitropropane,nitroisopropane, (nitromethyl)benzene, and the like. Exemplary carbonateesters include propylene carbonate, ethylene carbonate, butylenecarbonate and the like. In general, the amount of solvent or solventmixture employed for the reaction medium is not critical, so long as thereactive starting molecules and the base catalyst can be dissolved ordispersed, mixed or contacted with each other. Preferred solvents forthe reaction are polar aprotic solvents, such as nitrile solvents,amides solvents, and sulfur containing solvents. Particularly preferredsolvents are N,N-dimethylformamide and dimethylsulfoxide.

The polarity and solvation behaviour of the solvent might affect theobserved diastereoselectivity of the reaction. Without being bound to orlimited by any chemical theory or mechanistic proposal, it is possiblethat more polar solvents might better polarize the C—H bond of theactivated methylene of the compound of formula (II), increasing theproton tendency to interact with the base in the initial steps of thereaction. In the case of polar protic solvents, stronger solvationinteraction of the solvent with the base might interfere with theformation of compounds of formulae (VII)-(IX), leading to a lowerdiastereoselectivity of the reaction.

<Reaction Temperature and Reaction Time>

The useful reaction temperatures can vary widely, depending on thenature of the starting molecules and the desired product of thereaction. Since this invention provides a very effective method formaking homocyclic or heterocyclic compounds, most of the reactions canundergo efficiently with high yields and stereoselectivity within areasonable time interval (such as 1 to 5 hours) at ambient temperature,without the need of heating or cooling. So, from the economical point ofview, it is most desirable to perform the reaction without exercisingcontrol of the temperature, which is the most convenient and energysaving approach. In general, a temperature for the reaction may be inthe range from 0 to 45° C. Higher reaction temperatures may be used if ashorter reaction time is desirable. If compounds of formulae (IV) or (V)are desired, increasing the reaction temperature (for example in a rangefrom 50° C. to 140° C.) might be advisable. When a compound of formula(IV) is to be formed from a compound of formula (III) generated in situ,the subsequent heating step may be applied once the formation of thecompound of formula (III) is completed or is deemed satisfactory. Inother words, a compound of formula (III) may be formed first withoutheating or cooling, and heating may be applied only when a compound offormula (IV) is to be formed. In some embodiments, compound (IV) may beobtained directly from the reaction mixture of compounds (I) and (II) byperforming the reaction directly at effective elevated temperatures. Inother embodiments, compound (V) may be alternatively obtained by heatingcompounds (VI) at the effective elevated temperatures.

The useful reaction time to implement this invention can vary widely,depending on the nature of the starting molecules and the compound beingaimed for. When a compound of formula (III) is desired, a reaction timefrom 0.1 to 5 hours might be enough for most substrates, whilst forcompounds of formula (IV), the heating step might require a time from0.5 to 20 hours.

<Different Embodiments for the Reaction Procedure>

In some embodiments of the method to produce a homocyclic orheterocyclic compound, a compound of formula (I) is reacted with acompound of formula (II) in presence of a base.

Formula (I) and (II) are as defined above. The conjugate acid of thebase has a pK_(a) in the range of 1 to 15, more preferably in a range of1 to 13.5. In some embodiments, the base comprises a fluoride-containingbase. In some embodiments, the base comprises an organic fluoride saltor an inorganic fluorides salt. In some other embodiments, the base is atetraalkylammonium fluoride compound.

In some embodiments, the reaction is carried out in an aprotic solvent.In some other embodiments, the reaction may be carried out in a solventhaving a dielectric constant of at least 6. In some embodiments, ananhydrous solvent is used to carry out the reaction.

In some embodiments, the reaction is stirred at a temperature comprisedin a range from 0° C. to 45° C.

In some embodiments, a product of the reaction of a compound of formula(I) with a compound of formula (II) is a compound of formula (III).

In formula (III) G, n, R¹, R², R³, R⁴, and R⁵ are defined in the samemanner as in formulae (I) and (II). In some embodiments, thecyclopentene compounds of formula (III) are obtained as a racemicmixture.

In some embodiments, when in the compound of formula (III) G is NO₂, R⁴is a hydrogen, and n is 0 or 1, the compound of formula (III) may befurther reacted to obtain a compound of formula (IV).

In formula (IV), each of R¹, R², R³, R⁵, and n is the same as in thecompound of formula (III). In some embodiments, the compound of formula(III) is purified before being reacted to form a compound of formula(IV).

In some alternative embodiments, a compound of formula (V) is formed byreacting a compound of formula (VI).

Formula (V) and formula (VI) are as defined above. In some embodiments,the compound of formula (VI) is reacted at a temperature in a range from50° C. to 140° C.

In some embodiments, the compound of formula (VI) is reacted in presenceof a base, and a conjugated acid of the base has a pK_(a) in a rangefrom 1 to 15, more preferably in a range of 1 to 13.5. In some otherembodiments, the base comprises a fluoride-containing ion. In someembodiments, a ratio between a number of moles of the base and a numberof moles of the compound of formula (VI) is in a range from 0.001 to 10.

In some embodiments of the present disclosure, a reaction mixturecomprises a compound of formula (I), a compound of formula (II) and abase.

B, G, R¹, R², R³, R⁴, R⁵ and n are as defined above. The conjugated acidof the base has a pK_(a) in the range from 1 to 15, more preferably in arange of 1 to 13.5. In some embodiments, the base comprises afluoride-containing ion. In some other embodiments, the base is anorganic fluoride salt, such as a tetraalkylammonium fluoride compound.

In some embodiments, the reaction mixture comprises an aprotic solvent.In some other embodiments, the reaction mixture comprises a solventhaving a dielectric constant of at least 6. In some embodiments, thereaction mixture comprises an anhydrous solvent.

In some alternative embodiments, a reaction mixture comprises a compoundof formula (VI) and a base.

Formula (VI) is as defined above. The conjugated acid of the base has apK_(a) in the range of 1 to 15, more preferably in a range of 1 to 13.5.

In some embodiments, the base comprises a fluoride-containing ion. Insome embodiments, a ratio between a number of moles of the base and anumber of moles of the compound of formula (VI) is in a range from 0.001to 10, more preferably in a range of 0.001 to 0.5.

<Potential Applications>

The homocyclic or heterocyclic compounds prepared according to thepresent invention can be used for any purpose. For example, thecompounds prepared within this invention may be used in antibacterial,pesticides, insecticides, herbicidal, or medicinal compositions.Cyclopentene derivatives accessible through the method disclosed by thepresent invention may show modulating activity of chemokine receptors.As such, derivatives prepared according to the present invention may beused to treat inflammatory or allergic conditions in humans or otherspecies that would benefit from modulation of the activity of chemokinereceptors. Diseases or conditions that can be treated with chemokinereceptors inhibitors include anaphylactic or hypersensitizationresponses (e.g., allergies to drug, insect stings, or the like),inflammatory bowel diseases, autoimmune diseases (psoriasis, multipleSclerosis, rheumatoid or psoriatic arthritis, or the like), inflammatoryor allergic respiratory diseases and conditions (asthma, rhinitis,interstitials lung disease, or the like), inflammatory skin conditions(eczema, urticaria, or the like), eosinophilic conditions (eosinophilicfasciitis, myositis, pneumonia, or the like), or graft rejections.

Cyclopentadienone oximes accessible through the method disclosed by thepresent invention may show modulating activity for peroxisomeproliferated activated receptors (PPARs). Modulators of PPARs activitymay be used for treating various types of cancer and metabolic syndromes(e.g., diabetes, hyperinsulinism, arteriosclerosis obesity,hyperlipidemia, or the like).

EXAMPLES

The following examples are presented to more particularly illustrate thepresent invention, and should not be construed as limiting the scope andspirit of the present invention.

In the following examples, substituents are identified and referred towith the abbreviations reported in Table 1. In Table 1, * indicates abonding site of the substituent group.

TABLE 1 Abbreviations used to indicate substituent groups Abbreviation XY Z Structure Ph H H H

oBr Br H H mBr H Br H mCl H Cl H mNO₂ H NO₂ H mOMe H OMe H pBr H H BrpCF₃ H H CF₃ pCl H H Cl pDMA H H N(CH₃)₂ pDPA H H N(Ph)₂ pF H H F pMe HH Me pNO₂ H H NO₂ pOMe H H OMe BrOMe Br H OMe OMe2 OMe H OMe NAP

FUR PY Q = O Q = NH

CP

Tables 2 and 3 list the structures of the compounds (I-1) to (I-22) usedin the following examples.

TABLE 2 Structures of compounds (I-1) to (I-18) Compound R¹ B G (I-1) Ph trans-HC═CH NO₂ (I-2)  mOMe trans-HC═CH NO₂ (I-3)  pMe trans-HC═CHNO₂ (I-4)  pOMe trans-HC═CH NO₂ (I-5)  pDMA trans-HC═CH NO₂ (I-6)  pDPAtrans-HC═CH NO₂ (I-7)  oBr trans-HC═CH NO₂ (I-8)  mCl trans-HC═CH NO₂(I-9)  mNO₂ trans-HC═CH NO₂ (I-10) pCF₃ trans-HC═CH NO₂ (I-11) BrOMetrans-HC═CH NO₂ (I-12) OMe₂ trans-HC═CH NO₂ (I-13) NAP trans-HC═CH NO₂(I-14) FUR trans-HC═CH NO₂ (I-15) PY trans-HC═CH NO₂ (I-16) CPtrans-HC═CH NO₂ (I-17) pMe trans-HC═CH CHO (I-18) Ph C≡C (CO)Ph

TABLE 3 Structures of compounds (I-19) to (I-22) Compound Structure(I-19)

(I-20)

(I-21)

(I-22)

In Table 4 are listed the structures of the compounds (II-1) to (II-11)used in the following Examples.

TABLE 4 R³, R⁴ and R⁵ groups in compounds (II-1) to (II-11) Compound R³R⁴ R⁵ (II-1) Ph H CN (II-2) mBr H CN (II-3) mOMe H CN (II-4) pF H CN(II-5) pCl H CN (II-6) pBr H CN (II-7) pNO₂ H CN (II-8) pCF₃ H CN (II-9)pMe H CN  (II-10) pOMe H CN  (II-11) NAP H CN

<General Remarks>

Unless otherwise noted, all reactions were carried out under airatmosphere. All commercial reagents were used without furtherpurification, unless otherwise indicated. Solvents were used directlyfrom the purchased bottles.

Compounds of formulae (I-1) to (I-22) and formulae (II-1) to (II-11)were prepared according to literature procedures (Saleh et al.,Molecules, 2009, 14, 798; Abdelrazek et al., J. Heterocycl. Chem., 2014,57, 475; Rodriguez et al., Tetrahedron Lett., 2011, 52, 2629; andreferences therein).

The structures of the purified products were confirmed via ¹H, ¹³C,DEPT, NOESY NMR, X-ray crystallography, and high-resolution massspectrometry (HRMS).

Reported yields refer to isolated yield after purification.Diastereomeric ratios between compounds of formula (III) and compoundsof formula (III-B) were determined by ¹H NMR of the crude reactionmixture. Diastereomeric ratios between E and Z isomers for compounds offormula (IV) were determined by ¹H NMR of the crude mixture.

All NMR spectra were recorded on a Varian 400 MHz, Bruker 400 MHz,Bruker 500 MHz, and Brucker 600 MHz spectrometers using CDCl₃, CD₂Cl₂ ordeuterated dimethyl sulfoxide (DMSO-d₆) as deuterated solvents. Residualpeaks of the solvent were used as internal standard for calibration of¹H and ¹³C NMR spectra, whilst CFCl₃ (δ=0.00 ppm) was used for ¹⁹F NMRspectra as external standard.

Whenever crystal structures were deposited to the CambridgeCrystallographic Data Centre (CCDC), the CCDC reference code is reportedwith the crystal structure data.

<General Protocol GPI for the Reaction of Compounds of Formula (I) withCompounds of Formula (II)>

A round-bottom flask equipped with a magnetic stir bar was charged witha compound of formula (I) (0.27 mmol) and a compound of formula (II)(0.27 mmol, 1.0 equiv.) in 5 mL of solvent. In some instances, the colorof the reaction mixture changed from pale yellow to pale orange upon theaddition of base (0.05 equiv). The reaction mixture was stirred atambient temperature for a time in the range from 1 to 5 h. The progressof the reaction was monitored by thin layer chromatography (TLC, SiO₂,eluted with ethyl acetate:hexane, 30:70, volume:volume). In someinstances, as the reaction proceeded the color of the reaction mixtureturned gradually from pale orange to dark brown. After completedisappearance of the starting materials, the reaction was quenched bypouring into ice cold water, resulting in formation of a precipitate.The precipitate was dissolved in ethyl acetate (15 mL) and the organicphase was washed with water (2×12 mL). The organic phase was separatedand dried with anhydrous MgSO₄. The organic solvent was removed underreduced pressure and the obtained crude product was purified by columnchromatography on silica (100-200 mesh size) using an ethylacetate:hexane, 15:85 (volume:volume) mixture as eluent. Unlessotherwise stated, a racemate of compound (III) and a racemate of thecorresponding epimer (III-B) were obtained. Formation of a racemate wasconfirmed by single-crystal X-ray crystallography diffraction data andthe inability to rotate the polarization plane of plane-polarized light.

<General Protocol GPU for the Formation of Cyclopentadienone Oximes>

A round-bottom flask equipped with a magnetic stir bar was charged witha compound of formula (III) or (VI) (0.27 mmol) in DMSO (11 mL). In somecases, the color of the reaction mixture turned from pale yellow to paleorange upon addition of 1 M TBAF in THF (0.0054 mL, 2 mol %). Thereaction mixture was kept stirring at 75° C. for 6 h. The progress ofthe reaction was monitored by TLC (SiO₂, eluted with ethylacetate:hexane, 15:85, volume:volume). In some cases, the color of thereaction mixture turned from dark brown to dark reddish over time. Afterdisappearance of the starting material, the reaction was quenched bypouring into ice cold water, resulting in formation of a precipitate.The precipitate was dissolved in ethyl acetate (18 mL) and the organicphase was washed with water (2×12.5 mL). The organic phase was separatedand dried with anhydrous MgSO₄. The organic solvent was removed underreduced pressure and the crude product was purified by columnchromatography (SiO₂, 100-200 mesh, eluted with ethyl acetate:hexane,10:90, volume:volume).

Examples 1 to 8: Solvent Screening

For Examples 1 to 8, compound (1-1) was reacted with compound (II-1) toyield compounds (III-1) and (III-B-1) according to GP1. The reactions ofExamples 1 to Example 8 were performed using tetrabutylammonium fluoride(TBAF) as a base in the solvents indicated in Table 5. The reactionswere stirred for 5.0 hours at ambient temperature.

TABLE 5 Results of the solvent screening Dielectric Ratio Yield ExampleSolvent constant (III-1)/(III-B-1) (III-1) (%) 1 MeOH 33 50:50 44 2 EtOH25 50:50 42 3 2-Propanol 17.9 60:40 67 4 n-Butanol 17 74:26 60 5 THF 7.876:24 68 6 CH₃CN 38 79:21 72 7 DMF 37 91:9  87 8 DMSO 47 98:2  89

Racemate of 1-cyano-4-nitro-3,5-diphenylcyclopent-2-enecarboxamide(III-1)

Light brown solid, melting point: 163-165° C.;

¹H NMR (400 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 7.66 (d, J=7.4 Hz,2H), 7.58 (s, br, 1H, NH), 7.48 (s, br, 1H, NH), 7.45-7.42 (m, 5H),7.39-7.35 (m, 3H), 6.94 (s, 1H), 6.89 (d, J=6.0 Hz, 1H), 4.69 (d, J=6.0Hz, 1H);

¹³C NMR (100 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 164.6 (C), 143.7(C), 134.0 (C), 131.4 (C), 129.7 (CH), 129.6 (CH), 128.8 (2×CH), 128.5(3×CH), 128.4 (2×CH), 126.4 (2×CH), 118.6 (C), 93.9 (CH), 58.6 (C), 57.9(CH);

HRMS ESI (m/z): calculated for C₁₉H₁₅N₂O [M-NO₂]⁺ 287.1184, found287.1181.

The crystal structure of compound (III-1) is shown in FIG. 1. In Table 6are reported the crystal structure data with the correspondingrefinement parameters.

TABLE 6 Crystal structure data and refinement parameters for compound(III-1) CCDC Code 1585449 Crystal size 0.40 × 0.30 × 0.20 mm³ Empiricalformula C₁₉H₁₅N₃O₃ Theta range for 4.39 to data collection 66.41°.Formula weight 333.34 Index ranges −13 <= h <= 13, −8 <= k <= 8, −22 <=l <= 13 Temperature 100(2) K Reflections collected 10251 Wavelength1.54178 Å Independent 2807 reflections [R(int) = 0.0174] Crystal systemMonoclinic Completeness to 95.4% theta = 66.41° Space group P 1 21/n 1Absorption correction Semi-empirical from equivalents Unit cell a = Max.and min. 0.9493 and dimensions 11.4937(2) Å transmission 0.8718 b =Refinement method Full-matrix 7.5218(2) Å least-squares on F² c =Data/restraints/ 2807/0/226 19.3250(4) Å parameters α = 90.00° β =92.4950(10)° γ = 90.00° Volume 1669.13(6) Å³ Goodness-of-fit on F² 1.069Z 4 Final R indices R1 = [I > 2 sigma(I)] 0.0419, wR2 = 0.1078 Density1.327 Mg/m³ R indices R1 = (calculated) (all data) 0.0439, wR2 = 0.1095Absorption 0.755 mm⁻¹ Largest diff. 0.169 and −0.153 coefficient peakand hole e · Å⁻³ F(000) 696 CIF-ALERTS B

Racemate of 1-cyano-4-nitro-3,5-diphenylcyclopent-2-enecarboxamide(III-B-1)

Light brown solid, melting point: 184-186° C.;

¹H NMR (400 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 8.08 (s, br, 1H,NH), 8.02 (s, br, 1H, NH), 7.62 (d, J=8.0 Hz, 2H), 7.50-7.39 (m, 8H),7.01 (d, J=6.2 Hz, 1H), 6.86 (s, 1H), 4.78 (d, J=6.2 Hz, 1H);

¹³C NMR (100 MHz, DMSO-d₆, 5=39.5 ppm as standard): δ 165.4 (C), 143.0(C), 135.6 (C), 131.3 (C), 129.6 (CH), 128.9 (3×CH), 128.7 (2×CH), 128.6(3×CH), 126.4 (2×CH), 116.8 (C), 93.8 (CH), 59.6 (C), 55.4 (CH);

HRMS ESI (m/z): calculated for C₁₉H₁₅N₂O [M-NO₂]⁺ 287.1184, found287.1181.

The results in Table 5 indicate that the product (III-1) is formed inall the tested solvents, albeit with different yields and degrees ofdiastereoselectivity. The highest yields and ratios of compound (III-1)over (III-B-1) were obtained in Examples 5 to 8 with polar aproticsolvents. As by Example 8, DMSO yielded the highest yield anddiastereoselectivity amongst the tested solvents. Amongst proticsolvents, less polar solvents (n-butanol, 2-propanol) showed higherdiastereoselectivity than more polar ones (MeOH, EtOH). These resultsindicate that in polar protic solvents, stronger solvation of the basemight interfere with the interactions between the base and thereactants.

Examples 9 to 14: Use of Anhydrous Solvent

In Example 9 to Example 14, reactions between compounds of formulae (I)and (II) were run according to the general protocol GP1, in standardgrade DMSO and the results were compared with the same reaction run inanhydrous DMSO. Tetrabutylammonium fluoride (TBAF) was used as a base inall cases. The reactions were stirred for 5.0 hours at ambienttemperature.

TABLE 7 Effect of anhydrous solvents Standard DMSO Anhydrous DMSOCompound Compound Ratio Yield Ratio Yield Example (I) (II) Product(III)/(IIIB) (III)(%) (III)/(IIIB) (III) (%) 9 (I-1) (II-1) (III-1)98:2  89 >99:1  91 10 (I-1) (II-2) (III-2) 89:11 88 95:5 89 11 (I-1)(II-3) (III-3) 90:10 79 96:4 83 12 (I-3) (II-1) (III-4) 92:8  92 98:2 9413 (I-5) (II-1) (III-5) 89:11 78 94:6 80 14 (I-7) (II-1) (III-6) 92:8 75 95:5 81

Example 10: Racemate of3-(3-bromophenyl)-1-cyano-4-nitro-5-phenylcyclopent-2-enecarboxamide(III-2)

Brown solid, melting point: 192-194° C.;

¹H NMR (700 MHz, CDCl₃, δ=7.24 ppm as standard): δ 7.61 (s, 1H), 7.52(d, J=8.05 Hz, 1H), 7.47 (d, J=7.0 Hz, 2H), 7.41-7.38 (m, 3H), 7.35 (d,J=8.05 Hz, 1H), 7.26 (t, J=8.05 Hz, 1H), 6.68 (d, J=8.7 Hz, 1H), 6.27(s, 1H), 6.03 (s, br, 1H, NH), 5.41 (s, br, 1H, NH), 4.67 (d, J=8.7 Hz,1H);

¹³C NMR (175 MHz, CDCl₃, δ=77.0 ppm as standard): δ 164.8 (C), 145.6(C), 133.1 (CH), 132.9 (C), 130.9 (C), 130.6 (CH), 129.5 (CH), 129.3(2×CH), 129.2 (CH), 128.3 (2×CH), 127.6 (CH), 124.6 (CH), 123.2 (C),118.2 (C), 92.4 (CH), 59.6 (CH), 57.4 (C);

HRMS ESI (m/z): calculated for C₁₉H₁₅N₃O₃Br [M+H]⁺ 412.0297, found412.0294.

Example 11: Racemate of1-cyano-3-(3-methoxyphenyl)-4-nitro-5-phenylcyclopent-2-enecarboxamide(III-3)

Brown solid, melting point: 176-178° C.;

¹H NMR (700 MHz, CDCl₃, δ=7.24 ppm as standard): δ 7.48 (d, J=7.0 Hz,2H), 7.41-7.37 (m, 3H), 7.29 (t, J=7.7 Hz, 1H), 7.03 (d, J=7.7 Hz, 1H),6.96 (s, 1H), 6.92 (d, J=1.1 Hz, 1H), 6.72 (d, J=9.1 Hz, 1H), 6.24 (s,1H), 6.01 (s, br, 1H, NH), 5.30 (s, br, 1H, NH), 4.68 (d, J=9.1 Hz, 1H),3.81 (s, 3H);

¹³C NMR (175 MHz, CDCl₃, δ=77.0 ppm as standard): δ 164.9 (C), 159.9(C), 147.0 (C), 132.1 (C), 131.2 (C), 130.2 (CH), 129.4 (CH), 129.2(2×CH), 128.3 (2×CH), 126.3 (CH), 118.5 (C), 118.4 (CH), 116.0 (CH),111.4 (CH), 92.6 (CH), 59.7 (CH), 57.4 (C), 55.3 (OCH₃);

HRMS ESI (m/z): calculated for C₂₀H₁₈N₃O₄ [M+H]⁺ 364.1297, found364.1291.

Example 12: Racemate of1-cyano-4-nitro-3-phenyl-5-(p-tolyl)cyclopent-2-enecarboxamide (III-4)

Brown solid, melting point: 189-191° C.;

¹H NMR (600 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 7.65 (d, J=7.8 Hz,2H), 7.57 (s, br, 1H, NH), 7.45 (s, br, 1H, NH), 7.45-7.41 (m, 3H), 7.31(d, J=7.8 Hz, 2H), 7.16 (d, J=7.8 Hz, 2H), 6.93 (s, 1H), 6.85 (d, J=6.0Hz, 1H), 4.64 (d, J=6.0 Hz, 1H), 2.28 (s, 3H);

¹³C NMR (150 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 164.6 (C), 143.7(C), 137.9 (C), 131.4 (C), 130.9 (C), 129.7 (CH), 129.6 (CH), 129.1(2×CH), 128.9 (2×CH), 128.4 (2×CH), 126.4 (2×CH), 118.7 (C), 94.1 (CH),58.6 (C), 57.9 (CH), 20.7 (CH₃);

HRMS ESI (m/z): calculated for C₂₀H₁₇N₃O₃Na [M+Na]⁺ 370.1168, found370.1158.

Example 13: Racemate of1-cyano-5-(4-(dimethylamino)phenyl)-4-nitro-3-phenylcyclopent-2-enecarboxamide (III-5)

Brown solid, melting point: 201-203° C.;

¹H NMR (500 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 7.64 (d, J=7.0 Hz,2H), 7.58 (s, br, 1H, NH), 7.46-7.41 (m, 3H; s, br, 1H, NH), 7.23 (d,J=8.5 Hz, 2H), 6.91 (s, 1H), 6.78 (d, J=6.5 Hz, 1H), 6.67 (d, J=8.5 Hz,2H), 4.52 (d, J=6.5 Hz, 1H), 2.88 (s, 6H);

¹³C NMR (125 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 164.8 (C), 150.3(C), 143.8 (C), 131.5 (C), 129.61 (CH), 129.56 (CH), 129.2 (2×CH), 128.9(2×CH), 126.3 (2×CH), 120.4 (C), 118.9 (C), 111.9 (2×CH), 94.4 (CH),58.7 (CH), 58.4 (C), 39.7 (2×CH₃);

HRMS-ESI (m/z): calculated for C₂₁H₂₁N₄O₃ [M+H]⁺ 377.1614, found377.1612.

Example 14: Racemate of5-(2-bromophenyl)-1-cyano-4-nitro-3-phenylcyclopent-2-enecarboxamide(III-6)

Brown solid, melting point: 201-203° C.;

¹H NMR (600 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 7.71 (s, br, 1H,NH), 7.68 (dd, J=8.4, 1.2 Hz, 1H), 7.64 (dd, J=8.16, 1.8 Hz, 2H), 7.52(dd, J=8.4, 1.2 Hz, 1H), 7.50 (s, br, 1H, NH), 7.46-7.42 (m, 3H), 7.39(td, J=7.5, 1.2 Hz, 1H), 7.30 (td, J=7.5, 1.2 Hz, 1H), 6.95 (s, 1H),6.81 (d, J=6.0 Hz, 1H), 5.20 (d, J=6.0 Hz, 1H);

¹³C NMR (150 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 164.6 (C), 144.1(C), 133.7 (C), 133.1 (CH), 131.3 (C), 130.9 (CH), 130.0 (CH), 129.8(CH), 129.7 (CH), 129.1 (2×CH), 128.3 (CH), 126.8 (2×CH), 125.6 (C),118.5 (C), 95.8 (CH), 58.5 (C), 56.5 (CH);

HRMS ESI (m/z): calculated for C₁₉H₁₅BrN₃O₃ [M+H]⁺ 412.0297, found412.0251.

The results of Table 7 indicate that the use of anhydrous solvent mayfurther increase the observed diastereoselectivity and yield, suggestingthat water (a strongly solvating protic solvent with high dielectricconstant) might somewhat interfere with the reaction, probably throughinteraction with the base. In any case, according to the results inTable 7, standard grade solvents still perform remarkably well, and theuse of anhydrous solvent is not to be construed as a required limitationof the present disclosure.

Examples 15 to 25: Base Screening

In Example 15 to Example 25, compound (I-1) was reacted with compound(II-1) to yield compounds (III-1) and (III-B-1). The reactions describedin Example 9 to Example 19 were performed according to GP1 using DMSO assolvent and 100 mol % of the base indicated in Table 8. The reactionswere stirred for 1.0 h at standard ambient temperature, with theexceptions of Examples 19, 20, and 25, which were stirred for 24 hours.

TABLE 8 Results of base screening Ratio Yield Example Solvent(III-1)/(III-B-1) (III-1) (%) 15 TBAF 95:5  85 16 KF 82:18 67 17 CsF89:11 79 18 KHF₂ 83:17 62 19 TBAC — Traces 20 TBAB — Traces 21 DBU 58:4243 22 Et₃N 50:50 37 23 K₂CO₃ 51:49 35 24 NaOH  —^(a) 17 25 no base — notdetected ^(a)The product mixture was too complicated to be correctlyestimated. TBAC = tetrabutylammonium chloride; TBAB = tetrabutylammoniumbromide; DBU = (1,8-diazabicyclo[5.4.0]undec-7-ene).

The results in Table 8 indicate that a base is necessary for thereaction to proceed (cf. Example 25). The best results in terms ofobserved yield and diastereoselectivity were obtained in Examples 15 to18, when the base contained fluoride ions or was likely to releasefluoride ions in solution. The bases of Examples 16 to 18 were somewhatless soluble than TBAF in the solvent used, probably explaining theobserved differences with Example 15. Examples 19 and 20, in which atetrabutylammonium cation is used with different anions, further supportthis view. Using somewhat stronger bases as in Examples 21-23 stillproduced the compound of formula (III-1), albeit with poorerdiastereoselectivity and lower yields. When using very strong bases,such as metal hydroxides in Example 24, the product mixture becameincreasingly complicated, and the isolated yield significantly worse.

Examples 26 to 51: Reactions of Compounds (I) with Compounds (II)

In Examples 26 to Example 51, reactions between compounds of formulae(I) and (II) were run according to the general protocol GP1, in standardgrade DMSO and using tetrabutylammonium fluoride (TBAF) as a base in allcases. The reactions were stirred for 5.0 hours at ambient temperature.

TABLE 9 Results of Examples 26 to 51 Exam- Compound Compound Ratio Yieldple (I) (II) Product (III):(III-B) (III) (%) 26 (I-1)  (II-4) (III-7) 91:9 83 27 (I-1)  (II-5) (III-8)  95:5 89 28 (I-1)  (II-6) (III-9)  96:485 29 (I-1)  (II-7) (III-10) 91:9 86 30 (I-1)  (II-8) (III-11) 92:8 8031 (I-1)  (II-9) (III-12) 92:8 82 32 (I-1)   (II-10) (III-13) 92:8 77 33(I-1)   (II-11) (III-14)  90:10 88 34 (I-2)  (II-1) (III-15) 92:8 80 35(I-4)  (II-1) (III-16) 92:8 88 36 (I-6)  (II-1) (III-17) 91:9 85 37(I-8)  (II-1) (III-18) 96:4 90 38 (I-9)  (II-1) (III-19) 97:3 86 39(I-10) (II-1) (III-20) 99:1 80 40 (I-11) (II-1) (III-21)  89:11 82 41(I-12) (II-1) (III-22) 92:8 79 42 (I-13) (II-1) (III-23) 98:2 82 43(I-14) (II-1) (III-24)  90:10 72 44 (I-15) (II-1) (III-25) 91:9 79 45(I-16) (II-1) (III-26)  90:10 75 46 (I-17) (II-1) (III-27) >99:1  82 47(I-18) (II-1) (X-1)   — 92 48 (I-19) (II-1) (III-28) 95:5 79 49 (I-20)(II-1) (III-29)  84:16 75 50 (I-21) (II-1) (X-2)   — 78 51 (1-22) (II-1)(X-3)   — 87

Example 26: Racemate of1-cyano-3-(4-fluorophenyl)-4-nitro-5-phenylcyclopent-2-enecarboxamide(III-7)

Brown solid, melting point: 198-200° C.;

¹H NMR (500 MHz, CDCl₃, 3=7.24 ppm as standard): δ 7.47 (dd, J=8.5, 2.0Hz, 2H), 7.44 (dd, J=8.5, 5.0 Hz, 2H), 7.41-7.40 (m, 3H), 7.08 (t, J=8.7Hz, 2H), 6.69 (d, J=8.2 Hz, 1H), 6.19 (s, 1H), 6.02 (s, br, 1H, NH),5.33 (s, br, 1H, NH), 4.69 (d, J=8.2 Hz, 1H);

¹³C NMR (125 MHz, CDCl₃, 3=77.0 ppm as standard): δ 164.9 (C), 164.6 (d,J(C,F)=250.0 Hz, C), 146.0 (C), 131.1 (C), 129.5 (CH), 129.3 (2×CH),128.3 (2×CH), 128.1 (d, J(C,F)=8.7 Hz, 2×CH), 127.1 (d, J(C,F)=3.7 Hz,C), 126.1 (CH), 118.4 (C), 116.4 (d, J(C,F)=21.2 Hz, 2×CH), 92.6 (CH),60.0 (CH), 57.4 (C);

HRMS ESI (m/z): calculated for C₁₉H₁₅N₃O₃F [M+H]⁺ 352.1097, found352.1090.

Example 27: Racemate of3-(4-chlorophenyl)-1-cyano-4-nitro-5-phenylcyclopent-2-enecarboxamide(III-8)

Light brown solid, melting point: 203-205° C.;

¹H NMR (400 MHz, DMSO-d₆, 3=2.49 ppm as standard): δ 7.46 (d, J=7.6 Hz,2H), 7.45 (t, J=5.6 Hz, 1H), 7.40-7.37 (m, 4H), 7.39 (d, J=7.6 Hz, 2H),6.69 (d, J=8.4 Hz, 1H), 6.23 (s, 1H), 6.05 (s, br, 1H, NH), 5.50 (s, br,1H, NH), 4.67 (d, J=8.4 Hz, 1H);

¹³C NMR (100 MHz, DMSO-d₆, 3=39.5 ppm as standard): δ 164.9 (C), 145.8(C), 136.2 (C), 131.0 (C), 129.5 (CH), 129.4 (2×CH), 129.3 (C), 129.2(2×CH), 128.3 (2×CH), 127.4 (2×CH), 126.8 (CH), 118.3 (C), 92.5 (CH),59.6 (CH), 57.4 (C);

HRMS ESI (m/z): calculated for C₁₉H₁₄N₃O₃ClNa [M+Na]⁺ 390.0621, found390.0614.

Example 28: Racemate of3-(4-bromophenyl)-1-cyano-4-nitro-5-phenylcyclopent-2-enecarboxamide(III-9)

Brown solid, melting point: 187-189° C.;

¹H NMR (500 MHz, CDCl₃, δ=7.24 ppm as standard): δ 7.53 (d, J=8.5 Hz,2H), 7.47 (d, J=7.0 Hz, 2H), 7.42-7.38 (m, 3H), 7.31 (d, J=8.5 Hz, 2H),6.69 (d, J=8.75 Hz, 1H), 6.25 (s, 1H), 6.02 (s, br, 1H, NH), 5.32 (s,br, 1H, NH), 4.68 (d, J=8.75 Hz, 1H);

¹³C NMR (125 MHz, CDCl₃, δ=77.0 ppm as standard): δ 164.7 (C), 146.0(C), 132.3 (2×CH), 130.9 (C), 129.8 (C), 129.5 (CH), 129.3 (2×CH), 128.3(2×CH), 127.6 (2×CH), 126.8 (CH), 124.5 (C), 118.3 (C), 92.4 (CH), 59.7(CH), 57.4 (C);

HRMS ESI (m/z): calculated for C₁₉H₁₄N₃O₃BrNa [M+Na]⁺ 434.0116, found434.0106.

Example 29: Racemate of1-cyano-4-nitro-3-(4-nitrophenyl)-5-phenylcyclopent-2-enecarboxamide(III-10)

Brown solid, melting point: 173-175° C.;

¹H NMR (600 MHz, CDCl₃, δ=1.24 ppm as standard): δ 8.27 (d, J=8.4 Hz,2H), 7.63 (d, J=8.4 Hz, 2H), 7.49 (d, J=7.2 Hz, 2H), 7.44-7.41 (m, 3H),6.75 (d, J=9.1 Hz, 1H), 6.42 (s, 1H), 6.05 (s, br, 1H, NH), 5.35 (s, br,1H, NH), 4.70 (d, J=9.1 Hz, 1H);

¹³C NMR (150 MHz, CDCl₃, δ=77.0 ppm as standard): δ 164.3 (C), 148.6(C), 145.2 (C), 137.0 (C), 130.5 (C), 129.9 (CH), 129.7 (CH), 129.4(2×CH), 128.3 (2×CH), 127.2 (2×CH), 124.2 (2×CH), 117.9 (C), 92.3 (CH),60.4 (CH), 57.5 (C);

HRMS ESI (m/z): calculated for C₁₉H₁₅N₄O₅ [M+H]⁺ 379.1042, found379.1059.

Example 30: Racemate of1-cyano-4-nitro-5-phenyl-3-(4-(trifluoromethyl)phenyl)cyclopent-2enecarboxamide(III-11)

Brown solid, melting point: 179-181° C.;

¹H NMR (500 MHz, CDCl₃, δ=7.24 ppm as standard): δ 7.66 (d, J=8.25 Hz,2H), 7.57 (d, J=8.25 Hz, 2H), 7.49 (d, J=7.0 Hz, 2H), 7.447.40 (m, 3H),6.74 (d, J=9.0 Hz, 1H), 6.34 (s, 1H), 6.03 (s, br, 1H, NH), 5.32 (s, br,1H, NH), 4.70 (d, J=9.0 Hz, 1H);

¹³C NMR (125 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 164.2 (C), 142.4(C), 135.6 (C), 133.8 (C), 132.5 (CH), 129.5 (q, J(C,F)=32.2 Hz, C),128.6 (3×CH), 128.4 (2×CH), 127.3 (2×CH), 125.7 (2×CH), 124.0 (q,J(C,F)=270.6 Hz, CF₃), 118.3 (C), 93.6 (CH), 58.5 (C), 57.9 (CH);

¹⁹F NMR (471 MHz, DMSO-d₆, using CFCl₃ at δ=0.00 ppm as externalstandard) δ −61.2 (s, CF₃);

HRMS ESI (m/z): calculated for C₂₀H₁₅N₃O₃F₃ [M+H]⁺ 402.1066, found402.1059.

Example 31: Racemate of1-cyano-4-nitro-5-phenyl-3-(p-tolyl)cyclopent-2-enecarboxamide (III-12)

Light brown solid, melting point: 184-186° C.;

¹H NMR (400 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 7.57 (s, br, 1H,NH), 7.55 (d, J=8.0 Hz, 2H), 7.46 (s, br, 1H, NH), 7.42 (d, J=8.8 Hz,2H), 7.36-7.35 (m, 3H), 7.26 (d, J=8.0 Hz, 2H), 6.87 (s, 1H), 6.85 (d,J=5.6 Hz, 1H), 4.68 (d, J=5.6 Hz, 1H), 2.49 (s, 3H);

¹³C NMR (100 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 164.7 (C), 143.6(C), 139.4 (C), 134.1 (C), 129.4 (2×CH), 128.7 (CH), 128.6 (C), 128.5(3×CH), 128.4 (2×CH), 126.4 (2×CH), 118.7 (C), 94.1 (CH), 58.5 (C), 58.0(CH), 20.8 (CH₃);

HRMS ESI (m/z): calculated for C₂₀H₁₈N₃O₃ [M+H]⁺ 348.1348, found348.1339.

Example 32: Racemate of1-cyano-3-(4-methoxyphenyl)-4-nitro-5-phenylcyclopent-2-enecarboxamide(III-13)

Brown solid, melting point: 172-174° C.;

¹H NMR (700 MHz, CDCl₃, δ=7.24 ppm as standard): δ 7.46 (d, J=7.0 Hz,2H), 7.38 (d, J=8.75 Hz, 2H), 7.38-7.37 (m, 3H), 6.89 (d, J=8.75 Hz,2H), 6.68 (d, J=9.1 Hz, 1H), 6.12 (s, 1H), 6.02 (s, br, 1H, NH), 5.47(s, br, 1H, NH), 4.67 (d, J=9.1 Hz, 1H), 3.80 (s, 3H);

¹³C NMR (175 MHz, CDCl₃, δ=77.0 ppm as standard): δ 165.4 (C), 161.0(C), 146.3 (C), 131.5 (C), 129.3 (CH), 129.2 (2×CH), 128.3 (2×CH), 127.5(2×CH), 124.1 (CH), 123.3 (C), 118.6 (C), 114.5 (2×CH), 92.8 (CH), 59.6(CH), 57.4 (C), 55.4 (OCH₃);

HRMS ESI (m/z): calculated for C₂₀H₁₈N₃O₄ [M+H]⁺ 364.1297, found364.1291.

Example 33: Racemate of1-cyano-3-(naphthalen-2-yl)-4-nitro-5-phenylcyclopent-2-enecarboxamide(III-14)

Brown solid, melting point: 198-200° C.;

¹H NMR (600 MHz, CDCl₃, δ=7.24 ppm as standard): δ 7.88 (s, 1H), 7.86(d, J=9.0 Hz, 1H), 7.84-7.81 (m, 2H), 7.56 (dd, J=9.0, 1.8 Hz, 1H),7.53-7.50 (m, 4H), 7.43-7.39 (m, 3H), 6.86 (d, J=9.0 Hz, 1H), 6.37 (s,1H), 6.05 (s, br, 1H, NH), 5.36 (s, br, 1H, NH), 4.73 (d, J=9.0 Hz, 1H);

¹³C NMR (150 MHz, CDCl₃, δ=77.0 ppm as standard): δ 165.0 (C), 146.9(C), 133.8 (C), 133.0 (C), 131.3 (C), 129.4 (CH), 129.3 (2×CH), 129.1(CH), 128.6 (CH), 128.4 (2×CH), 128.2 (C), 127.7 (CH), 127.3 (CH), 126.9(CH), 126.5 (CH), 125.7 (CH), 123.3 (CH), 118.5 (C), 92.8 (CH), 59.8(CH), 57.6 (C);

HRMS ESI (m/z): calculated for C₂₃H₁₈N₃O₃ [M+H]⁺ 384.1348, found384.1354.

Example 34: Racemate of1-cyano-5-(3-methoxyphenyl)-4-nitro-3-phenylcyclopent-2-enecarboxamide(III-15)

Brown solid, melting point: 195-197° C. (79 mg, 80%);

¹H NMR (500 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 7.66 (d, J=7.0 Hz,2H), 7.62 (s, br, 1H, NH), 7.46 (s, br, 1H, NH), 7.45-7.42 (m, 3H), 7.28(t, J=8.0 Hz, 1H), 7.03 (s, 1H), 6.97 (d, J=8.0 Hz, 1H), 6.93 (s, 1H),6.92 (d, J=8.0 Hz, 1H), 6.88 (d, J=6.0 Hz, 1H), 4.66 (d, J=6.0 Hz, 1H),3.74 (s, 3H);

¹³C NMR (125 MHz, DMSO d₆, δ=39.5 ppm as standard): δ 164.6 (C), 159.0(C), 143.7 (C), 135.4 (C), 131.4 (C), 129.7 (CH), 129.6 (2×CH), 128.9(2×CH), 126.5 (2×CH), 120.7 (CH), 118.7 (C), 114.6 (CH), 113.7 (CH),94.0 (CH), 58.6 (C), 57.8 (CH), 55.0 (OCH₃);

HRMS ESI (m/z): calculated for C₂₀H₁₇N₂O₂ [M-NO₂]⁺ 317.1290, found317.1283.

Example 35: Racemate of1-cyano-5-(4-methoxyphenyl)-4-nitro-3-phenylcyclopent-2-enecarboxamide(III-16)

Brown solid, melting point: 207-209° C.;

¹H NMR (500 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 7.65 (d, J=7.0 Hz,2H), 7.59 (s, br, 1H, NH), 7.45-7.41 (m, 3H; s, br, 1H, NH), 7.36 (d,J=8.5 Hz, 2H), 6.93 (s, 1H), 6.92 (d, J=8.5 Hz, 2H), 6.83 (d, J=6.0 Hz,1H), 4.63 (d, J=6.0 Hz, 1H), 3.74 (s, 3H);

¹³C NMR (125 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 164.8 (C), 159.4(C), 143.8 (C), 131.5 (C), 129.9 (2×CH), 129.7 (2×CH), 128.9 (2×CH),126.5 (2×CH), 125.7 (C), 118.8 (C), 113.9 (2×CH), 94.3 (CH), 58.7 (C),57.8 (CH), 55.2 (OCH₃);

HRMS-EI (m/z): calculated for C₂₀H₁₇N₂O₂ [M-NO₂]⁺ 317.1290, found317.1285.

The crystal structure of compound (III-16) is shown in FIG. 2. In Table10 are reported the crystal structure data with the correspondingrefinement parameters.

TABLE 10 Crystal Structure data and refinement parameters for compound(III-16) CCDC Code 1045321 Crystal size 0.30 × 0.28 × 0.20 mm³ Empiricalformula C₂₀H₁₇N₃O₄ Theta range for data 1.747 to collection 26.398°.Formula weight 363.36 Index ranges −8 <= h <= 9, −12 <= k <= 12, −14 <=l <= 14 Temperature 100(2) K Reflections collected 13716 Wavelength0.71073 Å Independent 3592 reflections [R(int) = 0.0292] Crystal systemTriclinic Completeness to 99.6% theta = 25.242° Space group P -1Absorption correction Semi-empirical from equivalents Unit cell a = Max.and min. 0.9485 and dimensions 7.7378(2) Å transmission 0.8661 b =Refinement method Full-matrix 9.8726(3) Å least-squares on F² c =Data/restraints/ 3592/0/245 11.9093(4) Å parameters α = 86.5010(15)° β =78.2460(15)° γ = 81.6730(14)° Volume 880.84(5) Å³ Goodness-of-fit on F²1.133 Z 2 Final R indices R1 = [I > 2 sigma(I)] 0.0370, wR2 = 0.1132Density 1.370 Mg/m³ R indices (all data) R1 = (calculated) 0.0441, wR2 =0.1327 Absorption 0.097 mm⁻¹ Largest diff. 0.331 and −0.419 coefficientpeak and hole e · Å⁻³ F(000) 380 CIF-ALERTS C

Racemate of1-cyano-5-(4-methoxyphenyl)-4-nitro-3-phenylcyclopent-2-enecarboxamide(III-B-16)

Brown solid, melting point: 212-214° C. (yield=5%); ¹H NMR (500 MHz,DMSO-d₆, δ=2.49 ppm as standard): δ 8.04 (s, br, 1H, NH), 7.99 (s, br,1H, NH), 7.60 (d, J=7.7 Hz, 2H), 7.46-7.41 (m, 3H), 6.99-6.96 (m, 5H),6.81 (s, 1H), 4.70 (d, J=6.5 Hz, 1H), 3.77 (s, 3H);

¹³C NMR (125 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 165.6 (C), 159.4(C), 143.2 (C), 131.5 (C), 130.0 (2×CH), 129.7 (CH), 129.0 (2×CH), 128.7(CH), 127.2 (C), 126.4 (2×CH), 117.0 (C), 114.1 (2×CH), 94.1 (CH), 59.7(C), 55.2 (CH), 55.1 (OCH₃);

HRMS ESI (m/z): calculated for C₂₀H₁₇N₂O₂ [M-NO₂]⁺ 317.1290, found317.1285.

The crystal structure of compound (III-B-16) is shown in FIG. 3. InTable 11 are reported the crystal structure data with the correspondingrefinement parameters.

TABLE 11 Crystal structure data and refinement parameters for compound(III-B-16) CCDC Code 1045322 Crystal size 0.18 × 0.15 × 0.15 mm³Empirical formula C₂₀H₁₇N₃O₄ Theta range for data 1.72 to collection26.47°. Formula weight 363.36 Index ranges −7h <= 6, −24 <= , k <= 24−18 <= l <= 18 Temperature 296(2) K Reflections collected 27054Wavelength 0.71073 Å Independent reflections 3717 [R(int) = 0.0809]Crystal system Monoclinic Completeness to 98.6% theta = 26.47° Spacegroup P 1 21/c 1 Absorption correction Semi-empirical from equivalentsUnit cell a = Max. and min. 0.9486 and dimensions 6.299(2) Åtransmission 0.8545 b = Refinement method Full-matrix 19.711(6) Åleast-squares on F² c = Data/restraints/ 3717/0/246 14.744(5) Åparameters α = 90.00° β = 90.739(16)° γ = 90.00° Volume 1830.6(11) Å³Goodness-of-fit on F² 1.066 Z 4 Final R indices R1 = [I > 2 sigma(I)]0.0633, wR2 = 0.1816 Density 1.318 Mg/m³ R indices R1 = (calculated)(all data) 0.1387, wR2 = 0.2139 Absorption 0.094 mm⁻¹ Largest diff.0.259 and −0.194 coefficient peak and hole e · Å⁻³ F(000) 760 CIF-ALERTSC

Example 36: Racemate of1-cyano-5-(4-(diphenylamino)phenyl)-4-nitro-3-phenylcyclopent-2-enecarboxamide(III-17)

Brown solid, melting point: 198-200° C.;

¹H NMR (500 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 7.67 (s, br, 1H,NH), 7.64 (d, J=7.7 Hz, 2H), 7.46 (s, br, 1H, NH), 7.45-7.41 (m, 3H),7.31 (t, J=7.5 Hz, 6H), 7.06 (t, J=12 Hz, 2H), 7.00 (d, J=8.5 Hz, 4H),6.91 (s, 1H), 6.90 (d, J=7.7 Hz, 2H), 6.85 (d, J=5.7 Hz, 1H), 4.62 (d,J=5.7 Hz, 1H);

¹³C NMR (125 MHz, DMSO d₆, δ=39.5 ppm as standard): δ 164.8 (C), 147.4(C), 146.9 (2×C), 143.7 (C), 131.4 (C), 129.7 (7×CH), 129.65 (CH),129.62 (CH), 128.9 (2×CH), 127.4 (C), 126.5 (2×CH), 124.3 (3×CH), 123.5(2×CH), 122.2 (2×CH), 118.7 (C), 94.1 (CH), 58.7 (CH), 57.8 (C);

HRMS ESI (m/z): calculated for C₃₁H₂₅N₄O₃ [M+H]⁺ 501.1927, found501.1922.

Example 37: Racemate of5-(3-chlorophenyl)-1-cyano-4-nitro-3-phenylcyclopent-2-enecarboxamide(III-18)

Brown solid, melting point: 186-188° C.;

¹H NMR (600 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 7.67 (dd, J=8.4,1.5 Hz, 2H), 7.65 (s, br, 1H, NH), 7.54 (s, 1H), 7.52 (s, br, 1H, NH),7.47-7.38 (m, 6H), 6.94 (s, 1H), 6.93 (d, J=5.4 Hz, 1H), 4.78 (d, J=5.4Hz, 1H);

¹³C NMR (150 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 164.5 (C), 143.6(C), 136.6 (C), 132.9 (C), 131.4 (C), 130.2 (CH), 129.6 (2×CH), 128.8(2×CH), 128.5 (2×CH), 127.4 (CH), 126.5 (2×CH), 118.4 (C), 93.6 (CH),58.5 (C), 56.8 (CH);

HRMS ESI (m/z): calculated for C₁₉H₁₄ClN₃O₃Na [M+Na]⁺ 390.0621, found390.0624.

Example 38: Racemate of1-cyano-4-nitro-5-(3-nitrophenyl)-3-phenylcyclopent-2-enecarboxamide(III-19)

Brown solid, melting point: 196-198° C.;

¹H NMR (500 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 8.38 (s, 1H), 8.23(d, J=8.0 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.71-7.67 (m, 1H; s, br, 2H,NH), 7.61 (d, J=9.5 Hz, 2H), 7.48-7.42 (m, 3H), 7.02 (d, J=5.5 Hz, 1H),6.97 (s, 1H), 5.03 (d, J=5.5 Hz, 1H);

¹³C NMR (125 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 164.6 (C), 147.5(C), 143.7 (C), 136.6 (C), 135.6 (CH), 131.3 (C), 129.9 (CH), 129.71(CH), 129.69 (CH), 128.9 (2×CH), 126.6 (2×CH), 123.7 (CH), 123.5 (CH),118.3 (C), 93.6 (CH), 58.6 (C), 56.1 (CH);

HRMS ESI (m/z): calculated for C₁₉H₁₄N₄O₅Na [M+Na]⁺ 401.0862, found401.0856.

Example 39: Racemate of1-cyano-4-nitro-3-phenyl-5-(4-(trifluoromethyl)phenyl)cyclopent-2-enecarboxamide(III-20)

Brown solid, melting point: 204-206° C.;

¹H NMR (600 MHz, CDCl₃, δ=7.24 ppm as standard): δ 7.66 (d, J=8.4 Hz,2H), 7.63 (d, J=8.4 Hz, 2H), 7.44 (dd, J=6.6, 3.0 Hz, 2H), 7.40-7.39 (m,3H), 6.79 (d, J=8.4 Hz, 1H), 6.25 (s, 1H), 6.15 (s, br, 1H, NH), 5.52(s, br, 1H, NH), 4.72 (d, J=8.4 Hz, 1H);

¹³C NMR (150 MHz, CDCl₃, δ=77.0 ppm as standard): δ 164.8 (C), 146.9(C), 135.4 (C), 131.6 (q, J(C,F)=33.0 Hz, C), 130.6 (C), 130.3 (CH),129.1 (2×CH), 128.9 (3×CH), 126.1 (q, J(C,F)=3.7 Hz, 2×CH), 126.0(2×CH), 125.4 (q, J(C,F)=262.0 Hz, CF₃), 118.2 (C), 92.4 (CH), 59.0(CH), 57.3 (C);

HRMS-EI (m/z): calculated for C₂₀H₁₄F₃N₃O₃Na [M+Na]⁺ 424.0885, found424.0888.

Example 40:5-(2-bromo-4-methoxyphenyl)-1-cyano-4-nitro-3-phenylcyclopent-2-enecarboxamide(III-21)

Brown solid, melting point: 188-189° C.;

¹H NMR (400 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 7.77 (d, 2.4 Hz,1H), 7.66 (s, br, 1H, NH), 7.65 (d, J=8.4 Hz, 2H), 7.50 (d, J=8.8 Hz,1H), 7.47-7.41 (m, 3H), 7.26 (s, br, 1H, NH), 7.07 (d, J=7.0 Hz, 1H),7.02 (dd, J=8.8, 2.4 Hz, 1H), 6.84 (s, 1H), 4.86 (d, J=7.0 Hz, 1H), 3.80(s, 3H);

¹³C NMR (100 MHz, DMSO d₆, δ=39.5 ppm as standard): δ 164.6 (C), 156.7(C), 143.7 (C), 132.4 (CH), 131.3 (C), 131.3 (CH), 129.6 (CH), 129.3(C), 128.8 (2×CH), 126.5 (2×CH), 124.3 (C), 118.7 (C), 113.2 (CH), 111.8(CH), 93.4 (CH), 58.2 (C), 55.9 (CH), 51.6 (OCH₃);

HRMS-EI (m/z): calculated for C₂₀H₁₆BrN₃O₄Na [M+Na]⁺ 464.0222, found464.0201.

Example 41: Racemate of1-cyano-5-(3,4-dimethoxyphenyl)-4-nitro-3-phenylcyclopent-2-enecarboxamide(III-22)

Brown solid, melting point: 197-199° C.;

¹H NMR (600 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 7.66 (d, J=7.2 Hz,2H), 7.63 (s, br, 1H, NH), 7.47-7.41 (m, 5H), 7.08 (s, br, 1H, NH), 6.92(s, 2H), 6.87 (d, J=6.0 Hz, 1H), 4.61 (d, J=6.0 Hz, 1H), 3.745 (s, 3H),3.740 (s, 3H);

¹³C NMR (150 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 164.8 (C), 149.0(C), 148.3 (C), 143.8 (C), 131.5 (C), 129.6 (2×CH), 128.9 (2×CH), 126.4(2×CH), 126.0 (C), 121.0 (CH), 118.8 (C), 112.4 (CH), 111.4 (CH), 94.5(CH), 58.8 (C), 58.1 (CH), 55.4 (2×OCH₃);

HRMS-EI (m/z): calculated for C₂₁H₂₀N₃O₅ [M+H]⁺ 394.1403, found394.1399.

Example 42: Racemate of1-cyano-5-(naphthalen-2-yl)-4-nitro-3-phenylcyclopent-2-enecarboxamide(III-23)

Brown solid, melting point: 207-209° C.;

¹H NMR (400 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 8.04 (s, br, 1H,NH), 7.93-7.88 (m, 3H), 7.71 (dd, J=8.2, 1.4 Hz, 2H), 7.56-7.53 (m, 4H;s, br, 1H, NH), 7.50-7.44 (m, 3H), 7.05 (d, J=5.8 Hz, 1H), 7.00 (s, 1H),4.89 (d, J=5.8 Hz, 1H);

¹³C NMR (100 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 164.7 (C), 143.8(C), 132.8 (C), 132.5 (C), 131.6 (CH), 131.5 (CH), 129.8 (C), 129.7 (C),128.9 (2×CH), 128.0 (3×CH), 127.5 (CH), 126.6 (CH), 126.5 (2×CH), 126.5(CH), 126.1 (CH), 118.7 (C), 94.1 (CH), 58.8 (CH), 58.2 (C);

HRMS ESI (m/z): calculated for C₂₃H₁₈N₃O₃ [M+H]⁺ 384.1348, found384.1343.

Example 43: Racemate of1-cyano-5-(furan-2-yl)-4-nitro-3-phenylcyclopent-2-enecarboxamide(III-24)

Brown solid, melting point: 193-195° C.;

¹H NMR (400 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 7.67 (s, br, 1H,NH), 7.65 (dd, J=1.6, 0.8 Hz, 1H), 7.61 (dd, J=8.0, 1.6 Hz, 2H), 7.48(s, br, 1H, NH), 7.46-7.41 (m, 3H), 6.90 (s, 1H), 6.80 (d, J=6.2 Hz,1H), 6.56 (dd, 7=3.4, 0.8 Hz, 1H), 6.46 (dd, J=3.4, 1.6 Hz, 1H), 4.82(d, J=6.2 Hz, 1H);

¹³C NMR (150 MHz, CDCl₃, δ=77.0 ppm as standard): δ 164.8 (C), 146.6(C), 146.1 (C), 143.7 (CH), 130.6 (C), 130.2 (CH), 129.1 (2×CH), 126.5(CH), 126.1 (2×CH), 118.1 (C), 114.0 (CH), 109.9 (CH), 92.6 (CH), 55.8(C), 53.2 (CH);

HRMS ESI (m/z): calculated for C₁₇H₁₃N₂O₂ [M-NO₂]⁺ 277.0977, found277.0965.

Example 44: Racemate of1-cyano-4-nitro-3-phenyl-5-(1H-pyrrol-2-yl)cyclopent-2-ene-1-carboxamide(III-25)

Light Brown solid, melting point: 182-184° C.;

¹H NMR (500 MHz, CDCl₃, δ=7.24 ppm as standard): δ 10.85 (s, br, 1H,NH), 7.64 (s, br, 1H, NH), 7.57 (d, J=1.25 Hz, 2H), 7.46-7.41 (m, 3H),7.34 (s, br, 1H, NH), 6.87 (s, 1H), 6.72 (dd, J=3.5, 2.4 Hz, 1H), 6.70(d, J=7.0 Hz, 1H), 6.12 (dd, J=5.6, 2.4 Hz, 1H), 5.99 (dd, J=5.6, 3.5Hz, 1H), 4.67 (d, J=7.0 Hz, 1H);

¹³C NMR (125 MHz, CDCl₃, δ=77.0 ppm as standard): δ 164.9 (C), 143.7(C), 131.4 (C), 129.6 (CH), 129.4 (CH), 128.8 (2×CH), 126.2 (2×CH),123.1 (C), 118.6 (C), 118.5 (CH), 108.0 (CH), 107.8 (CH), 95.3 (CH),58.3 (C), 52.7 (CH);

HRMS ESI (m/z): calculated for C₁₇H₁₄N₄O₃Na [M+Na]⁺ 345.0964, found345.09521.

Example 45: Racemate of2′-bromo-2-cyano-5-nitro-4-phenyl-[1,1′-bi(cyclopentane)]-1′,3-diene-2carboxamide(III-26)

Brown liquid;

¹H NMR (600 MHz, CDCl₃, δ=7.24 ppm as standard): δ 7.41-7.36 (m, 5H),6.47 (s, br, 1H, NH), 6.27 (s, 1H), 6.21 (d, J=7.2 Hz, 1H), 5.96 (s, br,1H, NH), 4.65 (d, J=7.2 Hz, 1H), 2.71-2.68 (m, 2H), 2.47-2.44 (m, 2H),2.03-1.91 (m, 2H);

¹³C NMR (150 MHz, CDCl₃, δ=77.0 ppm as standard): δ 165.5 (C), 145.6(C), 133.0 (C), 130.7 (C), 130.1 (CH), 129.1 (2×CH), 127.6 (CH), 127.1(C), 126.1 (2×CH), 118.2 (C), 92.3 (CH), 55.4 (C), 54.0 (CH), 40.3(CH₂), 32.0 (CH₂), 22.3 (CH₂);

HRMS ESI (m/z): calculated for C₁₈H₁₆BrN₃O₃Na [M+Na]⁺ 424.0273, found424.0275.

Example 46: Racemate of1-cyano-4-formyl-3-phenyl-5-(p-tolyl)cyclopent-2-ene-1-carboxamide(III-27)

Brown solid, melting point: 187-189° C.;

¹H NMR (400 MHz, CDCl₃, δ=7.24 ppm as standard): δ 9.78 (s, 1H, CHO),7.49 (m, 5H), 7.07 (d, J=8.0 Hz, 2H), 7.03 (d, J=8.0 Hz, 2H), 5.90 (s,br, NH, 1H), 5.23 (s, br, NH, 1H), 4.92 (s, 1H), 4.20 (d, J=18.6, Hz,1H), 3.38 (d, J=18.6 Hz, 1H), 2.28 (s, 3H, CH₃);

¹³C NMR (100 MHz, CDCl₃, δ=77.0 ppm as standard): δ 188.2 (C), 165.4(C), 158.9 (C), 138.4 (C), 137.0 (C), 132.5 (C), 132.0 (CH), 130.6 (CH),129.4 (2×CH), 129.0 (2×CH), 128.9 (2×CH), 128.3 (2×CH), 122.0 (C), 60.4(CH), 50.7 (C), 45.4 (CH), 21.2 (CH₃);

HRMS ESI (m/z): calculated for C₂₁H₁₈N₂O₂Na [M+Na]⁺ 353.1266, found353.1252.

Example 47: Racemate of3-benzoyl-4-hydroxy-2,4-diphenylcyclopent-2-ene-1,1-dicarbonitrile (X-1)

Brown solid, melting point: 174-176° C.;

¹H NMR (600 MHz, CDCl₃, δ=7.24 ppm as standard): δ 7.60 (dd, 7=8.1, 1.09Hz, 2H), 7.50 (dd, 7=8.1, 1.09 Hz, 2H), 7.46 (dd, J=8.1, 1.5 Hz, 2H),7.34 (t, J=7.5 Hz, 1H), 7.30 (t, J=7.8 Hz, 2H), 7.25-7.21 (m, 4H), 7.17(t, 7=8.1 Hz, 2H), 4.54 (d, 0.9 Hz, 1H, OH), 3.37 (d, 7=14.4 Hz, 1H),3.16 (dd, 7=14.4, 0.9 Hz, 1H);

¹³C NMR (150 MHz, CDCl₃, δ=77.0 ppm as standard): δ 195.1 (C), 146.5(C), 141.9 (C), 140.9 (C), 134.6 (C), 134.2 (CH), 130.7 (CH), 130.0 (C),129.5 (2×CH), 129.1 (2×CH), 128.9 (4×CH), 128.4 (3×CH), 124.5 (2×CH),115.0 (C), 113.7 (C), 88.0 (C), 52.7 (CH₂), 42.4 (C);

HRMS ESI (m/z): calculated for C₂₆H₁₈N₂O₂Na [M+Na]⁺ 413.1266, found413.1274.

The crystal structure of compound (X-1) is shown in FIG. 4. In Table 12are reported the crystal structure data with the correspondingrefinement parameters.

TABLE 12 Crystal structure data and refinement parameters for compound(X-1) CCDC Code 1529387 Crystal size 0.30 × 0.25 × 0.15 mm³ Empiricalformula C₂₆H₁₉N₂O₂ Theta range for data 1.69 to collection 26.40°.Formula weight 391.43 Index ranges −10 <= h <= 10, −12 <= k <= 12, −16<= l <= 12 Temperature 100(2) K Reflections collected 16096 Wavelength0.71073 Å Independent 4181 reflections [R(int) = 0.0278] Crystal systemTriclinic Completeness to 99.5% theta = 26.40° Space group P -1Absorption correction Semi-empirical from equivalents Unit cell a = Max.and min. 0.9486 and dimensions 8.6603(3) Å transmission 0.8709 b =Refinement method Full-matrix 9.9536(4) Å least-squares on F² c =Data/restraints/ 4181/0/272 12.9050(4) Å parameters α = 108.153(2)° β =97.606(2)° γ = 98.766(2)° Volume 1025.38(6) Å³ Goodness-of-fit on F²1.041 Z 2 Final R indices R1 = 0.0418, [I > 2sigma(I)] wR2 = 0.1097Density 1.268 Mg/m³ R indices R1 = (calculated) (all data) 0.0497, wR2 =0.1154 Absorption 0.081 mm⁻¹ Largest diff. 0.238 and −0.892 coefficientpeak and hole e · Å⁻³ F(000) 410 CIF-ALERTS B

Example 48: Racemate of5-(4-((1R,2S,5S)-2-carbamoyl-2-cyano-5-nitro-4-phenylcyclopent-3-en-1yl)phenyl)-1-cyano-4-nitro-3-phenylcyclopent-2-enecarboxamide(III-28)

Brown solid, melting point: 208-210° C.:

¹H NMR (600 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 7.65 (d, J=7.2 Hz,2H), 7.64 (d, J=7.2 Hz, 2H), 7.56 (s, br, 2H, NH), 7.51-7.50 (m, 4H; 2H,NH), 7.47-7.41 (m, 6H), 6.97 (d, J=6.6 Hz, 1H), 6.95 (d, J=6.6 Hz, 1H),6.89 (s, 2H), 4.74 (d, J=6.6 Hz, 1H), 4.73 (d, J=6.6 Hz, 1H);

¹³C NMR (150 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 164.6 (2×C), 143.9(2×C), 133.9 (2×C), 131.5 (2×C), 129.6 (2×CH), 129.30 (2×CH), 129.25(2×CH), 128.9 (4×CH), 128.7 (2×CH), 126.3 (2×CH), 126.3 (2×CH), 118.7(C), 118.6 (C), 93.4 (CH), 93.3 (CH), 58.4 (C), 58.3 (C), 57.84 (CH),57.79 (CH);

HRMS ESI (m/z): calculated for C₃₂H₂₅N₆O₆ [M+H]⁺ 589.1836, found589.1847.

Example 49: Racemate of1-cyano-4-nitro-3-phenyl-5-((E)-styryl)cyclopent-2-enecarboxamide(III-29)

Light brown solid, melting point: 192-193° C.;

¹H NMR (700 MHz, DMSO-d₆, 3=2.49 ppm as standard): δ 7.88 (s, br, 1H,NH), 7.70 (s, br, 1H, NH), 7.58 (dd, J=9.8, 1.4 Hz, 2H), 7.45-7.41 (m,5H), 7.36 (t, J=8.4 Hz, 2H), 7.30 (t, J=8.4 Hz, 1H), 6.89 (s, 1H), 6.86(d, J=18.9 Hz, 1H), 6.50 (d, J=6.3 Hz, 1H), 6.28 (dd, 7=18.9 and 11.2Hz, 1H), 4.15 (dd, J=11.2, 6.3 Hz, 1H);

¹³C NMR (150 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 165.1 (C), 143.3(C), 135.8 (CH), 135.7 (C), 131.4 (C), 129.5 (2×CH), 128.8 (2×CH), 128.7(2×CH), 128.4 (CH), 126.6 (2×CH), 126.3 (2×CH), 122.5 (CH), 118.4 (C),94.5 (CH), 57.6 (C), 56.7 (CH);

HRMS ESI (m/z): calculated for C₂₁H₁₇N₂O [M-NO₂]⁺ 313.1341, found313.1336.

Example 50: Racemate of1-cyano-4-oxo-3-phenyl-2,4,5,6,7,7a-hexahydro-1H-indene-1-carboxamide(X-2)

Brown solid, melting point: 182-184° C.;

¹H NMR (600 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 7.77 (s, br, NH,1H), 7.73 (s, br, NH, 1H), 7.45 (dd, J=6.3, 3.3 Hz, 2H), 7.34-7.32 (m,3H), 3.73-3.71 (m, 1H), 3.58 (dd, J=17.4, 2.4 Hz, 1H), 3.33 (dd, J=17.4,1.2 Hz, 1H), 2.33-2.29 (m, 2H), 2.11-2.08 (m, 1H), 2.00-1.98 (m, 1H),1.82-1.74 (m, 1H) 1.51 (qd, J=12.6, 3.6 Hz, 1H);

¹³C NMR (150 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 199.0 (C), 166.5(C), 143.5 (C), 134.2 (C), 133.6 (C), 128.9 (CH), 128.2 (2×CH), 127.9(2×CH), 122.3 (C), 57.2 (CH), 47.8 (C), 45.4 (CH₂), 41.6 (CH₂), 27.2(CH₂), 23.0 (CH₂);

HRMS ESI (m/z): calculated for C₁₇H₁₇N₂O₂ [M+H]⁺ 281.1290, found281.1286.

The crystal structure of compound (X-2) is shown in FIG. 5. In Table 13are reported the crystal structure data with the correspondingrefinement parameters.

TABLE 13 Crystal structure data and refinement parameters for compound(X-2) CCDC Code 1529389 Crystal size 0.25 × 0.20 × 0.20 mm³ Empiricalformula C₁₇H₁₆N₂O₂ Theta range for data 2.50 to collection 26.42°.Formula weight 280.32 Index ranges −11 <= h <= 11, −11 <= k <= 11, 0 <=l <= 19 Temperature 296(2) K Reflections collected 5520 Wavelength0.71073 Å Independent 5531 reflections [R(int) = 0.0000] Crystal systemMonoclinic Completeness to 99.9% theta = 26.42° Space group P 1 21/n 1Absorption correction Semi-empirical from equivalents Unit cell a = Max.and min. 0.7454 and dimensions 9.3694(7) Å transmission 0.6515 b =Refinement method Full-matrix 9.4899(7) Å least-squares on F² c =Data/restraints/ 5531/0/191 15.8353(12) Å parameters α = 90.00° β =91.3220(10)° γ = 90.00° Volume 1407.62(18) Å³ Goodness-of-fit on F²0.982 Z 4 Final R indices R1 = 0.0529, [I > 2 sigma(I)] wR2 = 0.1428Density 1.323 Mg/m³ R indices R1 = (calculated) (all data) 0.0782, wR2 =0.1611 Absorption 0.088 mm⁻¹ Largest diff. 0.403 and −0.372 coefficientpeak and hole e · Å⁻³ F(000) 592 CIF-ALERTS B

Example 51: Racemate of(R)-4-cyano-6-hydroxy-2-phenyl-4H-chromene-4-carboxamide (X-3)

Brown solid, melting point: 191-193° C.;

¹H NMR (600 MHz, DMSO-d₆, d=2.49 ppm as standard): δ 9.68 (s, 1H, OH),7.83 (dd, J=7.8, 1.8 Hz, 2H), 7.81 (s, br, NH, 1H), 7.57 (s, br, NH,1H), 7.49-7.45 (m, 3H), 7.16 (d, J=7.5 Hz, 1H), 6.87 (s, 1H), 6.86 (d,J=7.5 Hz, 1H), 5.97 (s, 1H); ¹³C NMR (150 MHz, DMSO-d₆, δ=39.5 ppm asstandard): δ 168.6 (C), 154.1 (C), 149.7 (C), 141.7 (C), 132.4 (C),129.7 (CH), 128.5 (2×CH), 125.1 (2×CH), 119.5 (C), 118.7 (CH), 118.2(CH), 115.7 (C), 112.5 (CH), 91.6 (CH), 46.3 (C);

HRMS ESI (m/z): calculated for C₁₇H₁₃N₂O₃ [M+H]⁺ 293.0926, found293.0932.

The crystal structure of compound (X-3) is shown in FIG. 6. In Table 14are reported the crystal structure data with the correspondingrefinement parameters.

TABLE 14 Crystal structure data and refinement parameters for compound(X-3) CCDC Code 1529388 Crystal size 0.25 × 0.20 × 0.12 mm³ Empiricalformula C₁₇H₁₁N₂O₃ Theta range for data 1.44 to collection 26.79°.Formula weight 291.28 Index ranges −17 <= h <= 17, −9 <= k <= 8, −8 <= l<= 15 Temperature 100(2) K Reflections collected 9935 Wavelength 0.71073Å Independent 2801 reflections [R(int) = 0.0236] Crystal systemMonoclinic Completeness to 96.7% theta = 26.79° Space group P 1 21/c 1Absorption correction Semi-empirical from equivalents Unit cell a = Max.and min. 0.9486 and dimensions 14.165(15) Å transmission 0.8366 b =Refinement method Full-matrix 7.924(9) Å least-squares on F² c =Data/restraints/ 2801/0/199 12.147(12) Å parameters α = 90.00° β =94.54(2)° γ = 90.00° Volume 1359(3) Å³ Goodness-of-fit on F² 1.045 Z 4Final R indices R1 = 0.0595, [I > 2 sigma(I)] wR2 = 0.1472 Density 1.423Mg/m³ R indices R1 = (calculated) (all data) 0.0721, wR2 = 0.1573Absorption 0.100 mm⁻¹ Largest diff. 0.696 and −0.676 coefficient peakand hole e · Å⁻³ F(000) 604 CIF-ALERTS B

The results in Table 9 indicate that the reaction between a compound offormula (I) and a compound of formula (II) tends to proceed with highyields and high diastereoselectivity for a broad range of substituentson each starting monomer. The reaction proceeds satisfactorily also whenthe compound of formula (I) is a multifunctional nitrostyrene (compoundI-19), a conjugation extended nitrostyrene (I-20), or an α,β-unsaturatedcarbonyl compounds (cf. the cinnamaldehyde (I-17), the ynone (I-18),cyclohexenone (I-21), or 1,4-benzoquinone (I-22)). The fact that in thecase of Example 47 the observed product is a cyclopentanol preservingboth cyano groups suggests that the loss of the carbonyl oxygen and theformation of the carboxamide group might be tightly linked events.Formation of compound (X-2) in Example 50 indicates that differentprotons than the ones adjacent to the activated methylene compound mightbe lost during the elimination of the hydroxyl group formed by thecarbonyl of compound (II).

Examples 52 to 58: Preparation of Cyclopentadienone Oximes

Compounds (IV-1) to (VI-7) were prepared from the starting materialsindicated in Table 15 following the procedure outlined in GPU.

TABLE 15 Preparation of cyclopentadienone oximes Starting Ratio YieldExample material Product Z:E (IV) (%) 52 (III-1) (IV-1) 95:5 82 53(III-2) (IV-2) 95:5 80 54 (III-6) (IV-3) 99:1 78 55 (III-8) (IV-4) 92:872 56  (III-11) (IV-5) 96:4 80 57  (III-15) (IV-6) 95:5 78 58  (III-20)(IV-7) 92:8 76

Example 52: Preparation of(Z)-5-(hydroxyimino)-2,4-diphenylcyclopenta-1,3-diene-1-carbonitrile(IV-1)

The reaction was performed on a 1.5 mmol scale. The product was isolatedas a brick red solid.

¹H NMR (400 MHz, CDCl₃, δ=7.24 ppm as standard): δ 9.48 (s, OH), 7.97(dd, J=6.0, 3.0 Hz, 2H), 7.66 (dd, 7=8.0, 2.0 Hz, 2H), 7.22-7.51 (m,3H), 7.41-7.36 (m, 3H), 7.08 (s, 1H), n-Hexane grease (1.28, 0.82);

¹³C NMR (150 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 159.4 (C), 155.8(C), 140.5 (C), 132.2 (C), 131.7 (CH), 131.6 (C), 129.9 (CH), 129.2(2×CH), 129.0 (2×CH), 128.8 (CH), 128.5 (2×CH), 128.1 (2×CH), 117.6 (C),85.9 (C); HRMS ESI (m/z): calculated for C₁₈H₁₂N₂ONa [M+Na]⁺ 295.0847,found 295.0844.

The crystal structure of compound (IV-1) is shown in FIG. 7. In Table 16are reported the crystal structure data with the correspondingrefinement parameters.

TABLE 16 Crystal structure data and refinement parameters for compound(IV-1) CCDC Code 1816533 Crystal size 0.08 × 0.02 × 0.02 mm³ Empiricalformula C₃₆H₂₄N₄O₂ Theta range for data 1.604 to collection 26.438°.Formula weight 544.59 Index ranges −10 <= h <=11, −14 <= k <= 14, −15 <=l <= 16 Temperature 100(2) K Reflections collected 18753 Wavelength0.71073 Å Independent 5829 reflections [R(int) = 0.2110] Crystal systemTriclinic Completeness to 98.6% theta = 25.242° Space group P -1Absorption correction Semi-empirical from equivalents Unit cell a = Max.and min. 0.9485 and dimensions 9.390(3) Å transmission 0.7842 b =Refinement method Full-matrix 11.561(4) Å least-squares on F² c =Data/restraints/ 5329/0/381 12.824(4) Å parameters α = 82.956(6)° β =84.392(6)° γ = 74.505(6)° Volume 1328.3(8) Å³ Goodness-of-fit on F²0.984 Z 2 Final R indices R1 = 0.1028, [I > 2 sigma(I)] wR2 = 0.2404Density 1.362 Mg/m³ R indices R1 = (all data) 0.2526, (calculated) wR2 =0.3188 Absorption 0.086 mm⁻¹ Largest diff. 0.580 and −0.317 coefficientpeak and hole e · Å⁻³ F(000) 568 CIF-ALERTS B

Example 53: preparation of(Z)-4-(3-bromophenyl)-5-(hydroxyimino)-2-phenyl-cyclopenta-1,3-diene-1-carbonitrile(IV-2)

Brick red solid;

¹H NMR (400 MHz, CDCl₃, δ=7.24 ppm as standard): δ 9.28 (s, OH), 7.98(dd, J=6.2, 2.2 Hz, 2H), 7.84 (s, 1H), 7.61 (d, J=7.6 Hz, 1H), 7.53-7.48(m, 4H), 7.27 (d, J=7.6 Hz, 1H), 7.13 (s, 1H), n-Hexane grease (1.23,0.86);

¹³C NMR (125 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 159.1 (C), 155.4(C), 138.2 (C), 134.3 (C), 131.7 (CH), 131.40 (C), 131.31 (CH), 131.27(CH), 131.25 (CH), 130.5 (CH), 129.1 (2×CH), 128.1 (2×CH), 127.8 (CH),121.8 (C), 117.4 (C), 86.5 (C);

HRMS ESI (m/z): calculated for C₁₈H₁₂BrN₂O [M+H]⁺ 351.0133, found351.0128.

Example 54: preparation of(Z)-2-(2-bromophenyl)-5-(hydroxyimino)-4-phenylcyclopenta-1,3-diene-1-carbonitrile(IV-3)

Brick red solid;

¹H NMR (400 MHz, CDCl₃, δ=7.24 ppm as standard): δ 9.45 (s, OH), 7.70(d, J=8.0 Hz, 1H), 7.66 (dd, J=7.4, 1.2 Hz, 2H), 7.60 (d, J=7.6 Hz, 1H),7.45 (t, J=7.6 Hz, 1H), 7.41-7.32 (m, 4H), 7.02 (s, 1H), n-Hexane grease(1.24, 0.86);

¹³C NMR (100 MHz, CDCl₃, δ=77.0 ppm as standard): δ 162.9 (C), 156.1(C), 139.7 (C), 133.7 (CH), 133.5 (C), 132.0 (C), 131.8 (CH), 131.7(CH), 130.6 (CH), 129.0 (2×CH), 128.9 (CH), 128.5 (2×CH), 127.8 (CH),121.8 (C), 116.2 (C), 92.0 (C), n-Hexane grease (31.9, 29.7, 22.7,14.1);

HRMS ESI (m/z): calculated for C₁₈H₁₂BrN₂O [M+H]⁺ 351.0133, found351.0133.

The crystal structure of compound (IV-3) is shown in FIG. 8. In Table 17are reported the crystal structure data with the correspondingrefinement parameters.

TABLE 17 Crystal structure data and refinement parameters for compound(IV-3) CCDC Code 1817817 Crystal size 0.1 × 0.01 × 0.01 mm³ Empiricalformula C₁₈H₁₁BrN₂O Theta range for data 1.826 to collection 26.454°.Formula weight 351.20 Index ranges −4 <= h <= 4, −404 <= k <= 40, −13 <=l <= 13 Temperature 100(2) K Reflections collected 4971 Wavelength0.71073 Å Independent 2522 reflections [R(int) = 0.1070] Crystal systemMonoclinic Completeness to 91.9% theta = 25.242° Space group P 21/cAbsorption correction Semi-empirical from equivalents Unit cell a = Max.and min. 0.9485 and dimensions 3.8844(14) Å transmission 0.5512 b =Refinement method Full-matrix 32.965(10) Å least-squares on F² c =Data/restraints/ 2522/0/202 11.151(4) Å parameters α = 90° β = 90° γ =90° Volume 1427.8(8) Å³ Goodness-of-fit on F² 1.011 Z 4 Final R indicesR1 = 0.0865, [I > 2 sigma(I)] wR2 = 0.1733 Density 1.634 Mg/m³ R indicesR1 = (calculated) (all data) 0.1533, wR2 = 0.1999 Absorption 2.881 mm⁻¹Largest diff. 0.971 and −0.776 coefficient peak and hole e · Å⁻³ F(000)7048 CIF-ALERTS B

Example 55: preparation of(Z)-4-(4-chlorophenyl)-5-(hydroxyimino)-2-phenylcyclopenta-1,3-diene-1-carbonitrile(IV-4)

Brick red solid;

¹H NMR (400 MHz, DMSO-d₆, δ=2.49 ppm as standard): δ 8.05 (dd, J=6.0,3.2 Hz, 2H), 7.85 (d, J=8.6 Hz, 2H), 7.65 (s, 1H), 7.60-7.58 (m, 3H),7.51 (d, J=8.6 Hz, 2H);

¹³C NMR (100 MHz, DMSO-d₆, δ=39.5 ppm as standard): δ 159.2 (C), 155.6(C), 138.8 (C), 133.6 (C), 131.7 (C), 131.5 (C), 131.0 (CH), 130.6(2×CH), 130.4 (CH), 129.2 (2×CH), 128.5 (2×CH), 128.1 (2×CH), 117.5 (C),86.1 (C);

HRMS ESI (m/z): calcd for C₁₈H₁₂ClN₂O [M+H]⁺ 307.0638, found 307.0633.

Example 56: preparation of(Z)-5-(hydroxyimino)-4-(naphthalen-2-yl)-2-phenylcyclopenta-1,3-diene-1-carbonitrile(IV-5)

Brick red solid;

¹H NMR (500 MHz, CDCl₃, δ=7.24 ppm as standard): δ 8.23 (s, 1H), 8.01(dd, J=6.5 and 2.5 Hz, 2H), 7.83 (J=ddd, 8.5, 6.5, 2.5 Hz, 3H), 7.74(dd, J=8.5, 2.0 Hz, 1H), 7.53-7.52 (m, 3H), 7.49 (dd, J=6.25, 3.25 Hz,2H), 7.21 (s, 1H), n-Hexane grease (1.24, 0.86);

¹³C NMR (125 MHz, CDCl₃, δ=77.0 ppm as standard): δ 161.0 (C), 157.2(C), 141.7 (C), 133.4 (C), 133.2 (C), 131.8 (CH), 130.1 (CH), 129.4 (C),129.24 (C), 129.16 (2×CH), 128.98 (CH), 128.6 (CH), 128.2 (3×CH), 127.7(CH), 126.9 (CH), 126.5 (CH), 126.0 (CH), 117.7 (C), 87.8 (C), n-Hexanegrease (31.9, 29.7, 22.7, 14.1);

HRMS ESI (m/z): calcd for C₂₂H₁₅N₂O [M+H]⁺ 323.1184, found 323.1175.

Example 57: preparation of(Z)-5-(hydroxyimino)-2-(3-methoxyphenyl)-4-phenylcyclopenta-1,3-diene-1-carbonitrile(IV-6)

Brick red solid;

¹H NMR (400 MHz, CDCl₃, δ=7.24 ppm as standard): δ 9.71 (s, OH), 7.66(d, J=6.8 Hz, 2H), 7.55 (s, 1H), 7.51 (d, J=7.6 Hz, 1H), 7.43-7.34 (m,4H), 7.07 (m, 2H), 3.88 (s, 3H, OCH₃), n-Hexane grease (1.24, 0.86);n-Hexane grease (1.24, 0.86);

¹³C NMR (100 MHz, CDCl₃, δ=77.0 ppm as standard): δ 160.8 (C), 160.0(C), 157.0 (C), 141.8 (C), 133.0 (C), 132.1 (C), 130.1 (CH), 129.9 (CH),129.1 (CH), 129.0 (2×CH), 128.6 (2×CH), 120.7 (CH), 118.2 (CH), 117.7(C), 112.8 (CH), 87.7 (C), 55.5 (OCH₃), n-Hexane grease (29.7, 22.7,14.1);

HRMS ESI (m/z): calcd for C₁₉H₁₅N₂O₂ [M+H]⁺ 303.1134, found 303.1133.

Example 58: preparation of(Z)-5-(hydroxyimino)-4-phenyl-2-(4-(trifluoromethyl)phenyl)cyclopenta-1,3-diene-1-carbonitrile(IV-7)

Brick red solid;

¹H NMR (500 MHz, CD₂Cl₂, δ=5.30 ppm as standard): δ 9.44 (s, OH), 8.07(d, J=8.25 Hz, 2H), 7.79 (d, J=8.25 Hz, 2H), 7.69 (dd, J=7.75, 2.0 Hz,2H), 7.40-7.39 (m, 3H), 7.11 (s, 1H), n-Hexane grease (1.24, 0.86);

¹³C NMR (125 MHz, CDCl₃, δ=77.0 ppm as standard): δ 159.9 (C), 157.3(C), 142.4 (C), 135.7 (C), 132.9 (q, J(C,F)=32.5 Hz, C), 132.2 (C),130.0 (CH), 129.6 (CH), 129.4 (2×CH), 128.95 (2×CH), 128.88 (2×CH),126.42 (q, J(C,F)=269.2 Hz, CF₃), 126.40 (q, J(CH, F)=3.5 Hz, (2×CH)),117.1 (C), 89.6 (C), n-Hexane grease (30.1);

HRMS ESI (m/z): calcd for C₁₉H₁₂F₃N₂O [M+H]⁺ 341.0902, found 341.0902.

The results in Table 15 indicate that the disclosed method worksreliably for a variety of substitution patterns of the startingmaterial, yielding functionalized cyclopentadienone oximes in highyields and good diastereoselectivity.

The preferred embodiments of the disclosure were described, but thedisclosure is not limited to those. It is known to one skilled in theart that some modifications and variations may be made without departingfrom the spirit and scope of the present disclosure. Hence, the scope ofthe disclosure should be defined by the following claims.

What is claimed is:
 1. A method for producing a cyclic compound,comprising reacting a compound of formula (I) with a compound of formula(II) in presence of a base,

wherein in formula (I), B is substituted or unsubstituted vinylene,wherein the vinylene has n substituent(s) R² independently selected fromthe group consisting of deuterium, substituted and unsubstituted alkyl,alkenyl, alkynyl, alkenynyl, aryl, alkylaryl, arylalkyl, allyl, benzyl,cycloalkyl, cycloalkenyl, cycloalkynyl, cycloalkenynyl, alkanoyl,aryloyl, alkylsilyl, arylsilyl, alkoxysilyl, aryloxysilyl,alkoxycarbonyl, aryloxycarbonyl, heterocyclic ring, heteroaromatic ring,alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, esterderivatives, amide derivatives and metal salt derivatives of phosphonicacid group, phosphinic acid group, boric acid group, carboxylic acidgroup, sulfinic acid group, sulfonic acid group, sulfamic acid group andamino acid group, aliphatic moieties having a repeating unit of—(OCH₂CH₂)_(q)OCH₃, —(OCH₂CH(CH₃))_(q)OCH₃—(CH₂)_(q)CF₃, —(CF₂)_(q)CF₃or —(CH₂)_(q)CH₃, in which q=1, aliphatic chains having a moiety of(OR¹⁸)_(r)OR¹⁹, in which R¹⁸ is a divalent C₁₋₇ alkylene moiety, R¹⁹ isC₁₋₂₀ alkyl and 1≤r≤50, and substituent groups obtained by furthersubstituting the above mentioned substituent groups with ester group,amino acid group, halo, epoxy group, amino, amido, acyl, organosilyl,organotin, organogermyl, nitro, alkoxy, aryloxy, alkyl, aryl,heteroaryl, alkylthio, heteroarylthio, arylthiol, or an esterderivative, an amide derivative or a metal salt derivative of phosphonicacid group, phosphinic acid group, boric acid group, carboxylic acidgroup, sulfinic acid group, sulfonic acid group, sulfamic acid group oramino acid group, n is 0, 1 or 2, and when n is 2, the two R² may be thesame or different, and may joint together to form a ring; G is anelectron-withdrawing group selected from the group consisting ofoxygen-containing electron-withdrawing groups, nitrogen-containingelectron-withdrawing groups, sulfur-containing electron-withdrawinggroups, phosphorous-containing electron-withdrawing groups,electron-withdrawing aromatic groups, electron-withdrawingheteroaromatic groups, halogen-substituted alkyl groups, and halogenatoms; R¹ is hydrogen, or deuterium, or a substituent that is lesselectron-withdrawing than the electron-withdrawing group G, orunsubstituted alkyl, alkenyl, alkynyl, alkenynyl, aryl, alkylaryl,arylalkyl, allyl, benzyl, cycloalkyl, cycloalkenyl, cycloalkynyl,cycloalkenynyl, alkylsilyl, arylsilyl, alkoxysilyl or aryloxysilyl, or asubstituent obtained by substituting any of the above unsubstitutedgroups with epoxy, amino, organosilyl, organotin, organogermyl, alkoxy,aryloxy, alkyl, aryl, heteroaryl, alkylthio, heteroarylthio or arylthio;and two of R¹, R² and G may joint together to form a ring; in formula(II), each of R³ and R⁴ is independently hydrogen or a substituentselected from the group from which R² is selected, wherein R³ and R⁴ arethe same or different; R⁵ is an electron-withdrawing group selected fromthe group consisting of oxygen-containing electron-withdrawing groups,nitrogen-containing electron-withdrawing groups, sulfur-containingelectron-withdrawing groups, phosphorous-containing electron-withdrawinggroups, electron-withdrawing aromatic groups, electron-withdrawingheteroaromatic groups, halogen-substituted alkyl groups, and halogenatoms; and two of R³, R⁴ and R⁵ may joint together to form a ring; aconjugate acid of the base has a pK_(a) in a range of 1 to 15, whereinthe base is selected from the group consisting of bases containingcarbonate anion, bases containing bicarbonate anion, nitrogen-containingbases, and fluoride containing bases; and a product of the reaction ofthe compound of formula (I) with the compound of formula (II) is acompound of formula (III),

wherein in formula (III), G, n, R¹, R², R³, R⁴ and R⁵ are the same as informulae (I) and (II).
 2. The method of claim 1, wherein in formula(III), G is NO₂, R⁴ is H, and n is 0 or 1, the method further comprisingreacting the compound of formula (III) to obtain a compound of formula(IV)

wherein in formula (IV), R¹, R², R³, R⁵ and n are the same as in formula(III).
 3. The method of claim 2, further comprising purifying thecompound of formula (III) before reacting the compound of formula (III).4. A method of forming a compound of formula (V) by reacting a compoundof formula (VI),

wherein in formulae (V) and (VI), each of R⁶, R⁷ and R⁸ is independentlyhydrogen or a substituent, wherein R⁶, R⁷ and R⁸ are the same ordifferent; R⁹ is hydrogen, a substituent, or an electron withdrawinggroup selected from the group consisting of oxygen-containingelectron-withdrawing groups, nitrogen-containing electron-withdrawinggroups, sulfur-containing electron-withdrawing groups,phosphorous-containing electron-withdrawing groups, electron-withdrawingaromatic groups, electron-withdrawing heteroaromatic groups,halo-substituted alkyl groups, and halogen atoms; and two of R⁶, R⁷, R⁸,and R⁹ may joint together to form a ring.
 5. The method of claim 4,wherein the compound of formula (VI) is reacted in presence of a base,and a conjugate acid of the base has a pK_(a) in a range from 1 to 15.6. The method of claim 5, wherein the base comprises a fluoride ion. 7.A reaction mixture, comprising a compound of formula (VI) and a base,

wherein in formula (VI), each of R⁶, R⁷ and R⁸ is independently hydrogenor a substituent, wherein R⁶, R⁷ and R⁸ are the same or different; R⁹ ishydrogen, a substituent, or an electron withdrawing group selected fromthe group consisting of oxygen-containing electron-withdrawing groups,nitrogen-containing electron-withdrawing groups, sulfur-containingelectron-withdrawing groups, phosphorous-containing electron-withdrawinggroups, electron-withdrawing aromatic groups, electron-withdrawingheteroaromatic groups, halogen-substituted alkyl groups, and halogenatoms; and two of R⁶, R⁷, R⁸, and R⁹ may joint together to form a ring;and a conjugated acid of the base has a pK_(a) in a range from 1 to 15.8. The reaction mixture of claim 7, wherein the base comprises afluoride ion.
 9. The reaction mixture of claim 7, wherein a molar ratioof the base to the compound of formula (VI) is in a range of 0.001 to10.
 10. A compound of formula (V),

wherein in formula (V), each of R⁶, R⁷ and R⁸ is independently hydrogenor a substituent, wherein R⁶, R⁷ and R⁸ are the same or different; R⁹ ishydrogen, a substituent, or an electron withdrawing group selected fromthe group consisting of oxygen-containing electron-withdrawing groups,nitrogen-containing electron-withdrawing groups, sulfur-containingelectron-withdrawing groups, phosphorous-containing electron-withdrawinggroups, electron-withdrawing aromatic groups, electron-withdrawingheteroaromatic groups, halo-substituted alkyl groups, and halogen atoms;and two of R⁶, R⁷, R⁸, and R⁹ may joint together to form a ring.